Dasatinib Krka: Uses, Dosage & Side Effects
A potent BCR-ABL tyrosine kinase inhibitor for the treatment of chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL)
Dasatinib Krka is a prescription medication containing the active ingredient dasatinib, a second-generation BCR-ABL tyrosine kinase inhibitor (TKI). It is used for the treatment of chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) in adults and children aged 1 year and older. Dasatinib works by blocking the abnormal proteins that drive uncontrolled growth of leukemic cells, and is approximately 325-fold more potent than imatinib in laboratory studies. Regular blood monitoring is essential during treatment.
Quick Facts: Dasatinib Krka
Key Takeaways
- Dasatinib Krka is a second-generation tyrosine kinase inhibitor approved for chronic myeloid leukemia (CML) in all phases and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) in adults and children over 1 year.
- It is approximately 325 times more potent than imatinib in vitro and is effective against most imatinib-resistant BCR-ABL mutations, except T315I.
- Regular blood tests are essential during treatment, as dasatinib commonly causes myelosuppression (low blood counts), including neutropenia, thrombocytopenia, and anemia.
- Pleural effusion (fluid around the lungs) is a notable side effect that occurs more frequently in patients aged 65 and older; report any shortness of breath, chest pain, or persistent cough to your doctor immediately.
- Dasatinib must not be used during pregnancy unless clearly necessary, and both men and women should use effective contraception during treatment.
What Is Dasatinib Krka and What Is It Used For?
Dasatinib Krka is a targeted cancer therapy that contains dasatinib as its active ingredient. It belongs to the class of medications known as BCR-ABL tyrosine kinase inhibitors (TKIs), which represent a revolutionary approach to the treatment of certain types of leukemia. Dasatinib was originally developed by Bristol-Myers Squibb under the brand name Sprycel and received its first regulatory approval from the United States Food and Drug Administration (FDA) in 2006. Dasatinib Krka is a generic version manufactured by KRKA, d.d., Novo mesto, Slovenia, and contains the same active ingredient at the same strengths as the original product.
This medication is primarily used to treat chronic myeloid leukemia (CML), a cancer of the white blood cells. In CML, white blood cells called granulocytes begin to grow uncontrollably due to an abnormal protein produced by the Philadelphia chromosome, a genetic anomaly resulting from a translocation between chromosomes 9 and 22. This translocation creates the BCR-ABL fusion gene, which produces a constitutively active tyrosine kinase that drives the uncontrolled proliferation of leukemic cells. Dasatinib works by binding to and inhibiting this abnormal BCR-ABL kinase, effectively blocking the signal that tells cancer cells to divide and grow.
Dasatinib Krka is also approved for the treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) in adults, adolescents, and children aged 1 year and older, as well as lymphoid blast crisis CML in adults who have not responded to prior therapy. In Ph+ ALL, a different type of white blood cell called lymphocytes is produced in excessive quantities and survives longer than normal. By inhibiting the BCR-ABL kinase, dasatinib suppresses the growth of these leukemic lymphocytes as well.
What distinguishes dasatinib from the first-generation TKI imatinib is its significantly greater potency. In laboratory studies, dasatinib has been shown to be approximately 325 times more potent than imatinib in inhibiting BCR-ABL kinase activity. Additionally, dasatinib can bind to both the active and inactive conformations of the ABL kinase domain, which enables it to overcome many forms of imatinib resistance caused by mutations in the BCR-ABL protein. However, dasatinib is not effective against the T315I gatekeeper mutation, for which alternative agents such as ponatinib are required.
Beyond BCR-ABL, dasatinib also inhibits several other kinases, including SRC family kinases (SRC, LCK, YES, FYN), c-KIT, EPHA2, and platelet-derived growth factor receptor beta (PDGFR-beta). This multi-kinase inhibitory profile contributes to its clinical activity but may also be responsible for some of its distinctive side effects, such as pleural effusion and pulmonary arterial hypertension, which are thought to be related to SRC kinase inhibition in the pulmonary vasculature.
What Should You Know Before Taking Dasatinib Krka?
Contraindications
Dasatinib Krka must not be used if you are allergic (hypersensitive) to dasatinib or any of the other ingredients in the formulation. These inactive ingredients include lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, hydroxypropylcellulose, magnesium stearate, hypromellose, titanium dioxide (E171), and triacetin. If you think you might be allergic, consult your doctor before starting treatment.
Warnings and Precautions
Dasatinib may cause severe myelosuppression (low blood counts), pleural effusion (fluid around the lungs), pulmonary arterial hypertension, cardiac dysfunction, and serious hemorrhage. Regular blood monitoring and clinical assessments are essential. Report any breathing difficulties, unexplained bleeding, or signs of infection to your doctor immediately.
Before and during treatment with Dasatinib Krka, your doctor will monitor you carefully with regular blood tests and clinical examinations. Several important warnings and precautions apply to the use of this medication:
- Blood-thinning medications: If you are taking anticoagulants or antiplatelet drugs, inform your doctor, as dasatinib may increase the risk of bleeding.
- Liver or heart disease: Dasatinib should be used with caution if you have existing liver or heart conditions, or a history of such problems, as the medication can affect both organs.
- Breathing difficulties: If you develop shortness of breath, chest pain, or a persistent cough while taking Dasatinib Krka, contact your doctor immediately. These may be signs of fluid accumulation in the lungs or chest (pleural effusion), which is more common in patients aged 65 and older, or may indicate changes in the blood vessels supplying the lungs (pulmonary arterial hypertension).
- Hepatitis B: If you have ever had or currently have a hepatitis B infection, inform your doctor before starting treatment. Dasatinib Krka may cause reactivation of hepatitis B, which can be fatal in some cases. Your doctor will screen you for signs of this infection before treatment begins.
- Thrombotic microangiopathy (TMA): Contact your doctor if you develop bruising, bleeding, fever, fatigue, or confusion, as these may be signs of damage to blood vessels known as thrombotic microangiopathy.
You will have regular blood tests during treatment with Dasatinib Krka to check that the medication is working as expected and to monitor for side effects including low blood counts. Your doctor will also monitor your heart function and fluid balance. In children, bone growth and skeletal development will be assessed.
Children and Adolescents
Dasatinib Krka is approved for use in children and adolescents aged 1 year and older for the treatment of CML in the chronic phase and Ph+ ALL. It should not be given to children younger than 1 year, as clinical experience in this age group is limited. Bone growth and skeletal development will be monitored in children receiving dasatinib, as there have been reports of effects on bone metabolism including delayed growth plate fusion.
Pregnancy and Breastfeeding
Dasatinib Krka must not be used during pregnancy unless it is absolutely necessary and the potential benefits clearly outweigh the risks to the fetus. Animal studies have shown reproductive toxicity, and dasatinib can potentially cause harm to an unborn baby. If you are pregnant, think you may be pregnant, or are planning to become pregnant, tell your doctor immediately. Your doctor will discuss the potential risks of taking Dasatinib Krka during pregnancy with you.
Both women and men are advised to use effective contraception during treatment with Dasatinib Krka. Women of childbearing potential should use reliable contraception throughout the duration of treatment and for at least two weeks after the final dose.
Breastfeeding should be discontinued during treatment with Dasatinib Krka. It is not known whether dasatinib passes into human breast milk, but given the potential for serious adverse reactions in nursing infants, breastfeeding is not recommended during therapy.
Driving and Operating Machinery
If you experience side effects such as dizziness or blurred vision while taking Dasatinib Krka, you should exercise particular caution when driving or operating machinery. You are responsible for assessing whether you are in a fit condition to drive or perform tasks that require alertness. The effects and side effects of the medication described in this article may affect your ability to perform these activities safely.
Lactose and Sodium Content
Dasatinib Krka film-coated tablets contain lactose. If you have been told by your doctor that you have an intolerance to certain sugars, contact your doctor before taking this medication. The tablets also contain less than 1 mmol (23 mg) sodium per tablet, meaning they are essentially sodium-free.
How Does Dasatinib Krka Interact with Other Drugs?
Dasatinib is primarily metabolized in the liver by the cytochrome P450 enzyme CYP3A4. This means that medications which inhibit or induce CYP3A4 can significantly alter the blood levels of dasatinib, potentially leading to increased toxicity or reduced efficacy. It is essential to inform your doctor, pharmacist, or nurse about all medications, herbal remedies, and supplements you are taking or have recently taken.
Major Interactions — Do Not Use Together
| Interacting Drug | Type | Effect |
|---|---|---|
| Ketoconazole, Itraconazole | Strong CYP3A4 inhibitors | Significantly increase dasatinib blood levels, raising the risk of serious side effects including myelosuppression and fluid retention |
| Erythromycin, Clarithromycin, Telithromycin | CYP3A4 inhibitor antibiotics | Increase dasatinib exposure, potentially increasing toxicity |
| Ritonavir | Strong CYP3A4 inhibitor (antiviral) | Markedly increases dasatinib plasma concentrations |
| Phenytoin, Carbamazepine, Phenobarbital | Strong CYP3A4 inducers (antiepileptics) | Significantly decrease dasatinib blood levels, potentially rendering treatment ineffective |
| Rifampicin | Potent CYP3A4 inducer (anti-TB) | Dramatically reduces dasatinib plasma levels (by up to 82%), severely compromising efficacy |
| St. John’s Wort (Hypericum perforatum) | Herbal CYP3A4 inducer | Reduces dasatinib blood levels unpredictably; must not be used concurrently |
Minor Interactions — Use with Caution
| Interacting Drug | Type | Clinical Advice |
|---|---|---|
| Famotidine, Omeprazole | Acid-reducing agents (H2 blockers, PPIs) | Reduce dasatinib absorption by increasing gastric pH. Avoid concurrent use where possible. If an acid-reducing agent is required, use an antacid and separate by at least 2 hours. |
| Antacids (aluminum/magnesium hydroxide) | Direct acid neutralization | Do not take antacids from 2 hours before to 2 hours after taking Dasatinib Krka, as they reduce absorption. |
| Anticoagulants and antiplatelet drugs | Blood thinners | Increased risk of bleeding. Inform your doctor if you are taking any blood-thinning medication. Close monitoring is required. |
Do not consume grapefruit or grapefruit juice while taking Dasatinib Krka. Grapefruit inhibits CYP3A4 enzymes in the gut wall and liver, which can increase dasatinib blood levels and the risk of side effects.
What Is the Correct Dosage of Dasatinib Krka?
Dasatinib Krka will only be prescribed to you by a specialist physician with experience in the treatment of leukemia. Always take this medicine exactly as your doctor has instructed. If you are unsure about anything, consult your doctor or pharmacist. Dasatinib-containing products are taken orally once per day, either as tablets or as a powder for oral suspension.
Adults
Chronic Phase CML
The recommended starting dose is 100 mg once daily, taken at the same time each day. Your doctor may increase or decrease the dose depending on your response to treatment and any side effects.
Accelerated Phase CML, Blast Crisis CML, or Ph+ ALL
The recommended starting dose is 140 mg once daily. Your doctor may adjust the dose based on your clinical response and tolerability. For higher or lower doses, it may be necessary to combine tablets of different strengths.
Children and Adolescents (1 year and older)
The dosage for children with chronic phase CML or Ph+ ALL is based on body weight. Tablets are recommended for children weighing 10 kg or more, while the powder for oral suspension should be used for children weighing less than 10 kg or those who cannot swallow tablets. A dose adjustment may be necessary when switching between formulations.
| Body Weight (kg) | Daily Dose (mg) | Notes |
|---|---|---|
| 10 to under 20 kg | 40 mg | Tablets or oral suspension |
| 20 to under 30 kg | 60 mg | Tablets or oral suspension |
| 30 to under 45 kg | 70 mg | Tablets or oral suspension |
| 45 kg and over | 100 mg | Same as adult dose for chronic phase CML |
Tablets are not recommended for patients weighing less than 10 kg. The powder for oral suspension (10 mg/ml) should be used for these patients. Your doctor will calculate the appropriate dose based on your child's body weight.
Elderly Patients
No specific dose adjustment is required for elderly patients. However, patients aged 65 and older are at increased risk of developing pleural effusion (fluid around the lungs) and other fluid retention events. Close monitoring of respiratory symptoms is particularly important in this age group. Your doctor will carefully weigh the benefits and risks and may adjust the dose if necessary.
How to Take Dasatinib Krka
Take your tablets at the same time each day. Swallow the tablets whole with water. Do not crush, break, or chew the tablets, and do not disperse them in liquid. If you crush, split, or chew the tablets, you cannot be certain that you will receive the correct dose. Dasatinib Krka tablets can be taken with or without food. If a tablet is accidentally broken, other people handling the tablet should wear gloves to avoid direct skin contact with the medication.
Missed Dose
If you forget to take a dose of Dasatinib Krka, do not take a double dose to make up for the missed one. Simply take your next dose at the regular scheduled time. Taking a double dose increases the risk of serious side effects.
Overdose
If you take too much Dasatinib Krka, or if a child accidentally ingests the medication, contact your doctor, nearest hospital emergency department, or poison control center immediately. Medical attention may be necessary. Bring the medication package with you so healthcare professionals know what has been taken.
Duration of Treatment
Take Dasatinib Krka every day for as long as your doctor instructs you to continue. Treatment for chronic phase CML is typically long-term and may continue for several years. In some patients who achieve a deep and sustained molecular response (meaning the leukemia is barely detectable by highly sensitive laboratory tests), your doctor may discuss the possibility of treatment-free remission under careful monitoring. Never stop taking Dasatinib Krka on your own without consulting your doctor, as abruptly discontinuing treatment may allow the leukemia to return.
What Are the Side Effects of Dasatinib Krka?
Like all medications, Dasatinib Krka can cause side effects, although not everyone experiences them. Some side effects can be serious and require prompt medical attention. Your doctor will monitor you for side effects throughout your treatment with regular blood tests and clinical assessments.
Chest pain or difficulty breathing (may indicate pleural effusion or cardiac problems); unexpected bleeding or bruising without injury; blood in vomit, stool, or urine, or black-colored stools; signs of infection such as fever or severe chills; fever combined with mouth sores, throat pain, blistering or peeling of skin or mucous membranes.
Very Common Side Effects
May affect more than 1 in 10 people
- Infections (including bacterial, viral, and fungal infections)
- Shortness of breath (dyspnea)
- Diarrhea, nausea, vomiting
- Skin rash
- Fever (pyrexia)
- Swelling of face, hands, and feet (edema)
- Headache, fatigue, or weakness
- Bleeding events
- Muscle pain (during or after treatment), abdominal pain
- Low platelet count (thrombocytopenia)
- Low white blood cell count (neutropenia)
- Anemia (low red blood cell count)
- Pleural effusion (fluid around the lungs)
Common Side Effects
May affect up to 1 in 10 people
- Pneumonia, herpes virus infection (including CMV), upper respiratory tract infection
- Serious blood or tissue infection (including rare fatal cases)
- Palpitations, irregular heartbeat, heart failure, impaired heart function
- High blood pressure, pulmonary hypertension, cough
- Appetite disturbance, taste disturbance, bloating, colitis, constipation, heartburn
- Mouth ulcers, weight gain or loss, gastritis
- Tingling or numbness, itching, dry skin, acne, skin inflammation
- Tinnitus, hair loss, excessive sweating, vision problems (including blurred vision)
- Dry eyes, bruising, depression, insomnia, hot flushes, dizziness
- Joint pain, muscle weakness, chest pain, chills, muscle stiffness, muscle cramps
- Febrile neutropenia, gastrointestinal bleeding, elevated uric acid
- Fluid around the heart (pericardial effusion), irregular heart rhythm
Uncommon Side Effects
May affect up to 1 in 100 people
- Heart attack (sometimes fatal), pericarditis, angina, low blood pressure
- Airway constriction (bronchospasm), asthma
- Pancreatitis, peptic ulcer, esophagitis, abdominal swelling, difficulty swallowing
- Gallbladder inflammation, bile duct obstruction, gastroesophageal reflux
- Allergic reaction, anxiety, confusion, mood swings, fainting, tremor
- Eye inflammation, photosensitivity, hearing loss, nail problems
- Hand-foot syndrome, kidney failure, altered urination frequency
- Gynecomastia (breast enlargement in men), menstrual irregularities
- Hypothyroidism, osteonecrosis (bone death), joint inflammation
- Tumor lysis syndrome, low albumin, high cholesterol, swollen lymph nodes
- Cerebral hemorrhage, enlarged heart, liver inflammation, protein in urine
Rare Side Effects
May affect up to 1 in 1,000 people
- Right ventricular enlargement, myocarditis, cardiac arrest, coronary artery disease
- Blood clots (deep vein thrombosis), pulmonary embolism
- Malabsorption, bowel obstruction, anal fistula, impaired kidney function, diabetes
- Seizures, optic nerve inflammation, ataxia, difficulty walking
- Stroke, transient ischemic attack, facial paralysis, dementia
- Severe allergic reaction (anaphylaxis)
- Delayed epiphyseal fusion (bone growth plate), slowed growth
- Hyperthyroidism, thyroiditis, miscarriage
- Skin vasculitis, skin fibrosis
Inflammatory lung disease; gastrointestinal hemorrhage that may be fatal; reactivation of hepatitis B infection; skin reactions with fever, blisters, and mucous membrane ulcers; kidney disease with edema and abnormal laboratory results including protein in the urine and low blood protein; thrombotic microangiopathy (TMA) including decreased red blood cells, decreased platelets, and blood clot formation.
How Should You Store Dasatinib Krka?
Proper storage of Dasatinib Krka is essential to maintain the effectiveness and safety of the medication. Keep this medicine out of the sight and reach of children at all times. Children should never have unsupervised access to this medication, as accidental ingestion could be extremely dangerous.
Do not use Dasatinib Krka after the expiry date stated on the blister pack and the carton after "EXP." The expiry date refers to the last day of the stated month. No special storage conditions are required for this medication; it can be stored at room temperature.
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to dispose of medicines you no longer use. These measures will help protect the environment. Many pharmacies and hospitals have take-back programs for unused or expired medications.
What Does Dasatinib Krka Contain?
The active substance in Dasatinib Krka is dasatinib. Each film-coated tablet contains 20 mg, 50 mg, 70 mg, 80 mg, 100 mg, or 140 mg of dasatinib, depending on the tablet strength.
The other ingredients (excipients) are:
- Tablet core: Lactose monohydrate (200), microcrystalline cellulose (101 and 102), croscarmellose sodium, hydroxypropylcellulose (MW 80,000), magnesium stearate
- Film coating: Lactose monohydrate, hypromellose (15 mPas), titanium dioxide (E171), triacetin
Tablet Appearance
All Dasatinib Krka tablets are white to greyish-white, biconvex, and film-coated with "D7SB" engraved on one side and the strength number on the other. The tablets come in different shapes depending on the strength:
- 20 mg: Round tablet, approximately 5.6 mm diameter
- 50 mg: Oval tablet, approximately 11.0 mm length and 6.0 mm width
- 70 mg: Round tablet, approximately 9.1 mm diameter
- 80 mg: Triangular tablet, approximately 10.4 mm length and 10.6 mm width
- 100 mg: Oval tablet, approximately 15.1 mm length and 7.1 mm width
- 140 mg: Round tablet, approximately 11.7 mm diameter
All strengths of Dasatinib Krka are available in cartons containing 30 or 60 film-coated tablets in non-perforated blisters. Not all pack sizes may be marketed in every country.
Manufacturer
The marketing authorization holder is KRKA, d.d., Novo mesto, Slovenia. The tablets are manufactured at facilities in Spain (Synthon Hispania S.L., Barcelona), the Netherlands (Synthon BV, Nijmegen), Slovenia (KRKA, d.d., Novo mesto), and Croatia (KRKA-FARMA d.o.o., Jastrebarsko).
Frequently Asked Questions About Dasatinib Krka
Dasatinib Krka is used to treat chronic myeloid leukemia (CML) in adults, adolescents, and children older than 1 year. It is also used to treat Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) in adults and children aged 1 year and older, and lymphoid blast crisis CML in adults who have not responded to prior therapy. Dasatinib works by blocking the abnormal BCR-ABL protein that drives the uncontrolled growth of leukemic cells.
Both Dasatinib Krka and Sprycel contain the same active ingredient (dasatinib) at the same strengths and work in exactly the same way. Sprycel is the original brand-name product developed by Bristol-Myers Squibb, while Dasatinib Krka is a generic version manufactured by KRKA. Generic medicines must demonstrate bioequivalence to the reference product through rigorous regulatory evaluation, meaning they provide the same therapeutic effect. The main differences are the manufacturer, packaging, and typically cost, with generics often being more affordable.
Very common side effects (affecting more than 1 in 10 patients) include infections, shortness of breath, diarrhea, nausea, vomiting, skin rash, fever, swelling of face, hands and feet, headache, fatigue, bleeding, muscle pain, and abdominal pain. Blood test abnormalities such as low platelet count, low white blood cell count (neutropenia), anemia, and pleural effusion (fluid around the lungs) are also very common. Your doctor will monitor your blood counts regularly and adjust your dose if necessary.
Yes, dasatinib tablets can be taken with or without food. However, you should avoid grapefruit and grapefruit juice while taking dasatinib, as grapefruit can increase blood levels of the drug and potentially increase the risk of side effects. Tablets should be swallowed whole at the same time each day and should not be crushed, split, or chewed. Antacids should be avoided from 2 hours before to 2 hours after taking dasatinib.
Dasatinib is typically taken for an extended period, often for several years. The duration of treatment depends on your type of leukemia, your response to therapy, and your doctor's assessment. For chronic phase CML, treatment may continue indefinitely as long as it remains effective and tolerable. In some cases, patients who achieve a deep and sustained molecular response may be eligible for treatment-free remission under careful medical supervision. Never stop taking dasatinib without consulting your doctor, as abruptly discontinuing treatment may allow the leukemia to return.
If you miss a dose of dasatinib, do not take a double dose to compensate. Simply take your next scheduled dose at the usual time. Taking a double dose can increase the risk of serious side effects, including low blood counts and fluid retention. If you frequently forget doses, consider setting a daily alarm or using a pill organizer. Speak with your doctor or pharmacist if you are having difficulty remembering to take your medication.
References
- 1 European Medicines Agency (EMA). Dasatinib — Summary of Product Characteristics. EMA/CHMP, last updated 2024. Available from: ema.europa.eu
- 2 U.S. Food and Drug Administration (FDA). Sprycel (dasatinib) — Prescribing Information. Last revised 2024. Available from: fda.gov
- 3 Hochhaus A, et al. European LeukemiaNet 2020 recommendations for treating chronic myeloid leukemia. Leukemia. 2020;34(4):966-984. doi:10.1038/s41375-020-0776-2
- 4 National Comprehensive Cancer Network (NCCN). Clinical Practice Guidelines in Oncology: Chronic Myeloid Leukemia, Version 1.2025. Available from: nccn.org
- 5 Cortes JE, et al. Final 5-year study results of DASISION: The dasatinib versus imatinib study in treatment-naive chronic myeloid leukemia patients trial. J Clin Oncol. 2016;34(20):2333-2340. doi:10.1200/JCO.2015.64.8899
- 6 World Health Organization (WHO). WHO Model List of Essential Medicines — 23rd List, 2023. Geneva: WHO; 2023. Available from: who.int
- 7 Shah NP, et al. Dasatinib in imatinib-resistant or -intolerant chronic-phase, chronic myeloid leukemia patients: 7-year follow-up of study CA180-034. Am J Hematol. 2016;91(9):869-874. doi:10.1002/ajh.24423
- 8 Kantarjian HM, et al. Dasatinib or imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: 2-year follow-up from a randomized phase 3 trial (DASISION). Blood. 2012;119(5):1123-1129. doi:10.1182/blood-2011-08-376087
Editorial Team
This article has been medically reviewed and verified by the iMedic Medical Editorial Team, consisting of licensed specialist physicians in oncology, hematology, and clinical pharmacology with extensive experience in leukemia treatment and tyrosine kinase inhibitor therapy.
Content reviewed by board-certified specialists following ESMO, NCCN, and ELN (European LeukemiaNet) guidelines. All medical claims are supported by peer-reviewed evidence (Level 1A where available).
All content follows the GRADE evidence framework and is free from commercial funding or pharmaceutical industry influence. Regular updates ensure accuracy in line with the latest clinical guidelines.