Drugs List

Therapeutic Indications

Uses

Oral combination treatment of type 2 diabetes

Treatment of type 2 diabetes mellitus patients, particularly overweight patients, who have been unsuccessful in maintaining sufficient glycaemic control at their maximally tolerated dose of oral metformin monotherapy.

Contraindications

Acute alcohol intoxication
Children under 18 years
Elevated serum transaminases - greater than 2.5 times upper limit of normal
Hypovolaemic shock
Severe infection
Alcoholism
Bladder carcinoma
Breastfeeding
Cardiac failure
Dehydration
Diabetic pre-coma
Hepatic impairment
History of bladder carcinoma
History of cardiac failure
Pregnancy
Recent myocardial infarction
Renal impairment - glomerular filtration rate below 30ml/minute
Respiratory failure
Uninvestigated haematuria

Precautions and Warnings

Elderly
Polycystic ovarian syndrome
Poor cardiac reserve
Porphyria
Renal impairment - glomerular filtration rate 30 to 59 ml/minute

Not suitable for treatment of diabetic ketoacidosis
Reduce dose in patients with moderate renal impairment
Advise patient to take precautions to avoid hypoglycaemia whilst driving
Exclude bladder carcinoma before treatment
No experience with triple combination therapy with other oral antidiabetics
Test vit B12 levels if deficiency is suspected or risk factors are present
Assess risk of bladder cancer before treatment
Exclude pregnancy prior to initiation of treatment
Monitor renal function prior to initiating treatment
Perform liver function tests before commencing therapy and during therapy
If visual disturbances occur, perform ophthalmic evaluation
Investigate macroscopic haematuria
Monitor for development of lactic acidosis
Monitor liver function if fatigue or dark urine occurs
Monitor patient's weight
Monitor patients for signs and symptoms of cardiac failure
Monitor renal function 3 to 6 monthly in elderly patients
Monitor renal function 3- 6 monthly if renal function is borderline normal
Monitor renal function annually in patients with normal renal function
Review treatment 3-6 months after initiation
Treatment is associated with a reduction in haemoglobin levels
Advise patient to report symptoms of low vitamin B12 levels
Discontinue if any deterioration in cardiac status occurs
Increased incidence of fracture during pioglitazone therapy
Discontinue 48 hours before elective surgery with general anaesthesia
Advise patient to seek advice at first indications of pregnancy
Discontinue at first signs of jaundice
Discontinue if ALT level exceed 3 times the upper limit of normal & persist
Discontinue if lactic acidosis is suspected
Discontinue if patient is attempting to conceive
Pregnancy confirmed: Change patient to insulin treatment
Advise patient to avoid alcohol during treatment
Ovulation may resume in patients anovulatory due to insulin resistance
Advise patients to report bloody urine, dysuria or urinary urgency
Patient to inform DVLA if fitness to drive impaired or hypoglycaemic risk

Cases of cardiac failure have been reported when pioglitazone was used in combination with insulin, especially in patients with risk factors for cardiac failure. If this combination is prescribed, patients should be observed for symptoms of heart failure, including weight gain and oedema. Pioglitazone should be discontinued if there is any deterioration in cardiac symptoms.

Pioglitazone may cause fluid retention which may exacerbate or precipitate cardiac failure. Monitor patients for signs of cardiac failure, particularly those with diminished cardiac reserve. Discontinue if there is any deterioration in cardiac function.

Lactic acidosis can occur due to metformin accumulation. To reduce the incidence of this occurring, patients should be assessed for risk factors associated with the development of lactic acidosis and monitored regularly. Symptoms of lactic acidosis include acidotic dyspnoea, abdominal pain, hypothermia and coma. A diagnosis of lactic acidosis should be considered in the presence of non-specific symptoms such as muscle cramps, digestive disorders, abdominal pain or severe asthenia. Lactic acidosis is also indicated by decreased blood pH, plasma lactate levels above 5 mmol/L and an increased anion gap and lactate pyruvate ratio. If lactic acidosis is suspected, discontinue treatment and hospitalise the patient immediately. Risk factors for lactic acidosis include: poorly controlled diabetes, ketosis, prolonged fasting, excessive alcohol intake, hepatic impairment and any condition associated with hypoxia.

Patients who develop laboratory abnormalities or clinical illness (especially vague and poorly defined illness) should be evaluated promptly for evidence of ketoacidosis or lactic acidosis. Evaluation should include serum electrolytes and ketones, blood glucose and, if indicated, blood pH, lactate, pyruvate, and metformin levels. If acidosis occurs treatment with pioglitazone with metformin must be stopped immediately and other appropriate corrective measures initiated.

Intravascular administration of iodinated contrast agents can lead to renal failure which has been associated with lactic acidosis in patients receiving metformin. Pioglitazone with metformin therapy should be discontinued prior to, or at the time of the test and not reinstated until 48 hours afterwards and only after renal function has been re-evaluated and found to be normal.

Pioglitazone with metformin therapy should be discontinued 48 hours before elective surgery with general, spinal or epidural anaesthesia. Treatment should not usually be resumed earlier than 48 hours afterwards and only after renal function has been re-evaluated and found to be normal.

Pregnancy and Lactation

Pregnancy

Pioglitazone with metformin is contraindicated in pregnancy.

Insufficient information available relating to the use of pioglitazone during human pregnancy. Animal studies have shown foetotoxicity but no teratogenic effects of pioglitazone.

Metformin is generally considered to present a low risk when used during pregnancy and animal data generally do not indicate harmful effects on pregnancy, embryonal or foetal development, parturition or postnatal development. Metformin does cross the placenta, although it has been shown to be non-teratogenic in the majority of studies. One reference, however, suggests that metformin may be associated with growth retardation and hyperbilirubinaemia. Rare cases of neural tube defects and malformations of the heart and eye have been seen in animals though studies in pregnant women indicate a low risk to the foetus At the time of writing, current NICE guidelines on the treatment of diabetes during pregnancy recommend that metformin may be used as an adjunct or alternative to insulin in the pre-conception period and during pregnancy where the likely benefits from improved glycaemic control outweigh the potential for harm and informed consent is obtained from the mother. Metformin is not recommended for the treatment of diabetes in pregnancy as it does not provide adequate maternal glycaemic control and insulin therapy is preferred.

Detailed guidance on the treatment of diabetes during pregnancy is available from the National Institute for Health and Clinical Excellence (NICE) at https://www.nice.org.uk/guidance/CG63

Insulin is the treatment of choice for both Type 1 and Type 2 diabetes during pregnancy as it provides better control of maternal blood glucose compared to oral hypoglycaemics. It is believed that human insulin and insulin analogues do not cross the placenta, however there may be endogenous carrier proteins allowing passage of insulin to the embryo during early gestation; animal insulin is believed to cross the human placenta. The foetus produces its own insulin once insulin-secreting cells in the foetal pancreas become differentiated at the end of the first trimester.

Human insulin is considered safe to use during pregnancy and extensive experience with human insulin during pregnancy does not indicate any embryotoxic potential. Human insulin is often the first line treatment for diabetes and the benchmark used when comparing the safety of other insulins during pregnancy.

Infants of diabetic mothers are at an increased risk of congenital abnormalities, the rate of which appears to be related to maternal glycaemic control during the first trimester. Careful control of maternal blood glucose is required throughout pregnancy. Good maternal glycaemic control during labour and birth is important in preventing adverse neonatal outcomes including neonatal hypoglycaemia and respiratory stress.

The use of all medication in pregnancy should be avoided whenever possible; particularly in the first trimester. Non-drug treatments should also be considered. When essential, a medication with the best safety record over time should be chosen, employing the lowest effective dose for the shortest possible time. Polypharmacy should be avoided. Teratogens taken in the pre-embryonic period, often quoted as lasting until 14 to 17 days post-conception, are believed to have an all-or-nothing effect. Where drugs have a short half-life, and when the date of conception is certain, this may allow women to be reassured where drug exposure has occurred within this time frame. Further advice may be available from the UK National Teratology Information Service (NTIS) and through ToxBase, available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).

Lactation

Pioglitazone with metformin is contraindicated in breastfeeding.

In animal studies both pioglitazone and metformin have been detected in the milk of lactating rats.

At the time of writing, there are no reports of the use of pioglitazone during breastfeeding.

Metformin is excreted in breast milk although data indicates that infant exposure is low. Metformin has occasionally been detected in low-levels in the serum of breastfed infants although studies have found no adverse effects in infants breastfed by women taking metformin. LactMed (via ToxNet) recommends that caution be used in mothers with newborn and premature infants, and infants with renal impairment. Briggs and Schaefer both agree that metformin appears in breast milk at low concentrations and that it is considered compatible for use in breastfeeding mothers. LactMed (via ToxNet) states that maternal metformin levels are reasonably constant and therefore timing of breastfeeding with respect to dose is of little benefit. Current NICE guidelines state that women with pre-existing type 2 diabetes who are breastfeeding can resume or continue to take metformin immediately following birth. The manufacturer, however, recommends that the use of metformin should be avoided during breastfeeding.

Neonates, infants born prematurely, those with low birth weight, those with an unstable gastrointestinal function or who have serious illnesses may require special consideration. For any infant, if a drug is prescribed to the nursing mother, it should be at the lowest practical dose and for the shortest time. When drug administration is unavoidable and breastfeeding is to continue, minimisation of exposure of the infant to the drug may sometimes be achieved by timing the maternal doses to just after a feeding episode. Infants exposed to drugs via breast milk should be monitored for unusual signs or symptoms. Interactions between the drug received by the infant from the mother's milk and medication prescribed for the infant should also be considered, for example, when the drug given to the infant may prevent metabolism of the drug received via breast milk.
Specialist advice is available from the UK Drugs in Lactation Advisory Service at https://www.midlandsmedicines.nhs.uk/content.asp?section=6&subsection=17&pageIdx=1

Side Effects

Abdominal pain
Allergic reaction
Altered liver function tests
Anaemia
Anaphylaxis
Angioedema
Arthralgia
Bladder cancer
Blood lipid changes
Decreased appetite
Decreased vitamin-B12 absorption
Diarrhoea
Dizziness
Erectile dysfunction
Erythema
Fatigue
Flatulence
Fluid retention
Haematuria
Headache
Hepatic impairment
Hepatitis
Hypersensitivity reactions
Hypoaesthesia
Hypoglycaemia
Increased risk of fractures
Insomnia
Lactic acidosis
Macular oedema
Nausea
Oedema
Proteinuria
Pruritus
Sinusitis
Sweating
Taste disturbances
Upper respiratory tract infection
Urticaria
Vertigo
Visual disturbances
Vomiting
Weight gain

Presentation

Tablets containing pioglitazone with metformin

Drugs List

Therapeutic Indications

Uses

Oral combination treatment of type 2 diabetes

Treatment of type 2 diabetes mellitus patients, particularly overweight patients, who have been unsuccessful in maintaining sufficient glycaemic control at their maximally tolerated dose of oral metformin monotherapy.

Dosage

Adults

Elderly

Patients with Renal Impairment

Additional Dosage Information

Contraindications

Acute alcohol intoxication
Children under 18 years
Elevated serum transaminases - greater than 2.5 times upper limit of normal
Hypovolaemic shock
Severe infection
Alcoholism
Bladder carcinoma
Breastfeeding
Cardiac failure
Dehydration
Diabetic pre-coma
Hepatic impairment
History of bladder carcinoma
History of cardiac failure
Pregnancy
Recent myocardial infarction
Renal impairment - glomerular filtration rate below 30ml/minute
Respiratory failure
Uninvestigated haematuria

Precautions and Warnings

Elderly
Polycystic ovarian syndrome
Poor cardiac reserve
Porphyria
Renal impairment - glomerular filtration rate 30 to 59 ml/minute

Not suitable for treatment of diabetic ketoacidosis
Reduce dose in patients with moderate renal impairment
Advise patient to take precautions to avoid hypoglycaemia whilst driving
Exclude bladder carcinoma before treatment
No experience with triple combination therapy with other oral antidiabetics
Test vit B12 levels if deficiency is suspected or risk factors are present
Assess risk of bladder cancer before treatment
Exclude pregnancy prior to initiation of treatment
Monitor renal function prior to initiating treatment
Perform liver function tests before commencing therapy and during therapy
If visual disturbances occur, perform ophthalmic evaluation
Investigate macroscopic haematuria
Monitor for development of lactic acidosis
Monitor liver function if fatigue or dark urine occurs
Monitor patient's weight
Monitor patients for signs and symptoms of cardiac failure
Monitor renal function 3 to 6 monthly in elderly patients
Monitor renal function 3- 6 monthly if renal function is borderline normal
Monitor renal function annually in patients with normal renal function
Review treatment 3-6 months after initiation
Treatment is associated with a reduction in haemoglobin levels
Advise patient to report symptoms of low vitamin B12 levels
Discontinue if any deterioration in cardiac status occurs
Increased incidence of fracture during pioglitazone therapy
Discontinue 48 hours before elective surgery with general anaesthesia
Advise patient to seek advice at first indications of pregnancy
Discontinue at first signs of jaundice
Discontinue if ALT level exceed 3 times the upper limit of normal & persist
Discontinue if lactic acidosis is suspected
Discontinue if patient is attempting to conceive
Pregnancy confirmed: Change patient to insulin treatment
Advise patient to avoid alcohol during treatment
Ovulation may resume in patients anovulatory due to insulin resistance
Advise patients to report bloody urine, dysuria or urinary urgency
Patient to inform DVLA if fitness to drive impaired or hypoglycaemic risk

Cases of cardiac failure have been reported when pioglitazone was used in combination with insulin, especially in patients with risk factors for cardiac failure. If this combination is prescribed, patients should be observed for symptoms of heart failure, including weight gain and oedema. Pioglitazone should be discontinued if there is any deterioration in cardiac symptoms.

Pioglitazone may cause fluid retention which may exacerbate or precipitate cardiac failure. Monitor patients for signs of cardiac failure, particularly those with diminished cardiac reserve. Discontinue if there is any deterioration in cardiac function.

Lactic acidosis can occur due to metformin accumulation. To reduce the incidence of this occurring, patients should be assessed for risk factors associated with the development of lactic acidosis and monitored regularly. Symptoms of lactic acidosis include acidotic dyspnoea, abdominal pain, hypothermia and coma. A diagnosis of lactic acidosis should be considered in the presence of non-specific symptoms such as muscle cramps, digestive disorders, abdominal pain or severe asthenia. Lactic acidosis is also indicated by decreased blood pH, plasma lactate levels above 5 mmol/L and an increased anion gap and lactate pyruvate ratio. If lactic acidosis is suspected, discontinue treatment and hospitalise the patient immediately. Risk factors for lactic acidosis include: poorly controlled diabetes, ketosis, prolonged fasting, excessive alcohol intake, hepatic impairment and any condition associated with hypoxia.

Patients who develop laboratory abnormalities or clinical illness (especially vague and poorly defined illness) should be evaluated promptly for evidence of ketoacidosis or lactic acidosis. Evaluation should include serum electrolytes and ketones, blood glucose and, if indicated, blood pH, lactate, pyruvate, and metformin levels. If acidosis occurs treatment with pioglitazone with metformin must be stopped immediately and other appropriate corrective measures initiated.

Intravascular administration of iodinated contrast agents can lead to renal failure which has been associated with lactic acidosis in patients receiving metformin. Pioglitazone with metformin therapy should be discontinued prior to, or at the time of the test and not reinstated until 48 hours afterwards and only after renal function has been re-evaluated and found to be normal.

Pioglitazone with metformin therapy should be discontinued 48 hours before elective surgery with general, spinal or epidural anaesthesia. Treatment should not usually be resumed earlier than 48 hours afterwards and only after renal function has been re-evaluated and found to be normal.

Pregnancy and Lactation

Pregnancy

Pioglitazone with metformin is contraindicated in pregnancy.

Insufficient information available relating to the use of pioglitazone during human pregnancy. Animal studies have shown foetotoxicity but no teratogenic effects of pioglitazone.

Metformin is generally considered to present a low risk when used during pregnancy and animal data generally do not indicate harmful effects on pregnancy, embryonal or foetal development, parturition or postnatal development. Metformin does cross the placenta, although it has been shown to be non-teratogenic in the majority of studies. One reference, however, suggests that metformin may be associated with growth retardation and hyperbilirubinaemia. Rare cases of neural tube defects and malformations of the heart and eye have been seen in animals though studies in pregnant women indicate a low risk to the foetus At the time of writing, current NICE guidelines on the treatment of diabetes during pregnancy recommend that metformin may be used as an adjunct or alternative to insulin in the pre-conception period and during pregnancy where the likely benefits from improved glycaemic control outweigh the potential for harm and informed consent is obtained from the mother. Metformin is not recommended for the treatment of diabetes in pregnancy as it does not provide adequate maternal glycaemic control and insulin therapy is preferred.

Detailed guidance on the treatment of diabetes during pregnancy is available from the National Institute for Health and Clinical Excellence (NICE) at https://www.nice.org.uk/guidance/CG63

Insulin is the treatment of choice for both Type 1 and Type 2 diabetes during pregnancy as it provides better control of maternal blood glucose compared to oral hypoglycaemics. It is believed that human insulin and insulin analogues do not cross the placenta, however there may be endogenous carrier proteins allowing passage of insulin to the embryo during early gestation; animal insulin is believed to cross the human placenta. The foetus produces its own insulin once insulin-secreting cells in the foetal pancreas become differentiated at the end of the first trimester.

Human insulin is considered safe to use during pregnancy and extensive experience with human insulin during pregnancy does not indicate any embryotoxic potential. Human insulin is often the first line treatment for diabetes and the benchmark used when comparing the safety of other insulins during pregnancy.

Infants of diabetic mothers are at an increased risk of congenital abnormalities, the rate of which appears to be related to maternal glycaemic control during the first trimester. Careful control of maternal blood glucose is required throughout pregnancy. Good maternal glycaemic control during labour and birth is important in preventing adverse neonatal outcomes including neonatal hypoglycaemia and respiratory stress.

The use of all medication in pregnancy should be avoided whenever possible; particularly in the first trimester. Non-drug treatments should also be considered. When essential, a medication with the best safety record over time should be chosen, employing the lowest effective dose for the shortest possible time. Polypharmacy should be avoided. Teratogens taken in the pre-embryonic period, often quoted as lasting until 14 to 17 days post-conception, are believed to have an all-or-nothing effect. Where drugs have a short half-life, and when the date of conception is certain, this may allow women to be reassured where drug exposure has occurred within this time frame. Further advice may be available from the UK National Teratology Information Service (NTIS) and through ToxBase, available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).

Lactation

Pioglitazone with metformin is contraindicated in breastfeeding.

In animal studies both pioglitazone and metformin have been detected in the milk of lactating rats.

At the time of writing, there are no reports of the use of pioglitazone during breastfeeding.

Metformin is excreted in breast milk although data indicates that infant exposure is low. Metformin has occasionally been detected in low-levels in the serum of breastfed infants although studies have found no adverse effects in infants breastfed by women taking metformin. LactMed (via ToxNet) recommends that caution be used in mothers with newborn and premature infants, and infants with renal impairment. Briggs and Schaefer both agree that metformin appears in breast milk at low concentrations and that it is considered compatible for use in breastfeeding mothers. LactMed (via ToxNet) states that maternal metformin levels are reasonably constant and therefore timing of breastfeeding with respect to dose is of little benefit. Current NICE guidelines state that women with pre-existing type 2 diabetes who are breastfeeding can resume or continue to take metformin immediately following birth. The manufacturer, however, recommends that the use of metformin should be avoided during breastfeeding.

Neonates, infants born prematurely, those with low birth weight, those with an unstable gastrointestinal function or who have serious illnesses may require special consideration. For any infant, if a drug is prescribed to the nursing mother, it should be at the lowest practical dose and for the shortest time. When drug administration is unavoidable and breastfeeding is to continue, minimisation of exposure of the infant to the drug may sometimes be achieved by timing the maternal doses to just after a feeding episode. Infants exposed to drugs via breast milk should be monitored for unusual signs or symptoms. Interactions between the drug received by the infant from the mother's milk and medication prescribed for the infant should also be considered, for example, when the drug given to the infant may prevent metabolism of the drug received via breast milk.
Specialist advice is available from the UK Drugs in Lactation Advisory Service at https://www.midlandsmedicines.nhs.uk/content.asp?section=6&subsection=17&pageIdx=1

Counselling

Taking this product with or shortly after food may help reduce gastrointestinal discomfort associated with oral metformin.

Remind patients that adherence to a calorie controlled diet is an essential part of their treatment.

Advise patients with polycystic ovarian syndrome that ovulation may occur as a result of improved insulin action. These patients should be made aware of the risk of pregnancy and advised to use appropriate contraception.

Advise patient to seek advise at the first indications of pregnancy.

Advise patients to report blood in urine, painful urination or urinary urgency to their doctor immediately.

Advise patient to report symptoms of low vitamin B12 levels.

Patients should avoid alcohol.

Advise patients that their ability to drive or operate machinery may be impaired.

Advise patient to take precautions to avoid hypoglycaemia when driving.

Inform the patient that he/she needs to inform the Driving and Vehicle Licensing Agency (DVLA) about the medication they are receiving. The Drivers Medical Group at the DVLA will be able to advise the patient on the legal issues surrounding the treatment of diabetes mellitus and driving.

The DVLA can be contacted by post at the following address:

Drivers Medical Group, DVLA, Swansea, SA99 1TU

By phone on 0870 600 0301; or by fax on 0845 850 0095

Detailed guidance on eligibility to drive, and precautions required, is available from the DVLA.

https://www.gov.uk/government/publications/at-a-glance

Further information concerning diabetes and driving may be obtained from the DVLA website at:

https://www.gov.uk/government/organisations/driver-and-vehicle-licensing-agency

Side Effects

Abdominal pain
Allergic reaction
Altered liver function tests
Anaemia
Anaphylaxis
Angioedema
Arthralgia
Bladder cancer
Blood lipid changes
Decreased appetite
Decreased vitamin-B12 absorption
Diarrhoea
Dizziness
Erectile dysfunction
Erythema
Fatigue
Flatulence
Fluid retention
Haematuria
Headache
Hepatic impairment
Hepatitis
Hypersensitivity reactions
Hypoaesthesia
Hypoglycaemia
Increased risk of fractures
Insomnia
Lactic acidosis
Macular oedema
Nausea
Oedema
Proteinuria
Pruritus
Sinusitis
Sweating
Taste disturbances
Upper respiratory tract infection
Urticaria
Vertigo
Visual disturbances
Vomiting
Weight gain

Overdosage

It is strongly recommended that the UK National Poisons Information Service be consulted on cases of suspected or actual overdose where there is doubt over the degree of risk or about appropriate management.

The following number will direct the caller to the relevant local centre (0844) 892 0111

Information may be obtained if you have access to ToxBase the primary clinical toxicology database of the National Poisons Information Service. This is available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).

Further Information

Last Full Review Date: October 2014

Reference Sources

Drugs During Pregnancy and Lactation: Treatment Options and Risk Assessment, 2nd edition (2007) ed. Schaefer, C., Peters, P. and Miller, R. Elsevier, London.

Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk, 9th edition (2011) ed. Briggs, G., Freeman, R. and Yaffe, S. Lippincott Williams & Wilkins, Philadelphia.

Joint Formulary Committee. British National Formulary (online) London: BMJ Group and Pharmaceutical Press. Accessed on 10 October 2014.

Medications and Mothers' Milk, 14th Edition (2010) Hale, T. Hale Publishing, Amarillo, Texas.

NICE Clinical Guideline 63. Diabetes in Pregnancy: Management of Diabetes and its Complications from Pre-conception to the Postnatal Period. Issue Date: March 2008 (reissued July 2008)

Summary of Product Characteristics: Competact 15 mg/850 mg film-coated tablets. Takeda UK Ltd. Revised December 2016.

US National Library of Medicine. Toxicology Data Network. Drugs and Lactation Database (LactMed).
Available at: https://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?LACT
Pioglitazone. Last revised: 07 September 2013
Metformin. Last revised: 07 September 2013
Last accessed: 08 October 2014

MHRA August 2011
https://www.mhra.gov.uk/Safetyinformation/DrugSafetyUpdate/CON125962
Last accessed: 10 October 2014

EMA Safety Update December 2016
Available at: https://www.ema.europa.eu/ema/
Last accessed: 18 January 2017

MHRA Drug Safety Update June 2022
Available at: https://www.mhra.gov.uk
Last accessed: 21 July 2022