Source: Health Products Regulatory Authority (ZA) Revision Year: 2023 Publisher: CIPLA MEDPRO (PTY) LTD., Building 9, Parc du Cap, Mispel Street, Bellville, 7530, RSA Company Contact Details: Phone: +27 21 943 4200 Customer Care: 080 222 6662
[PROPRIETARY NAME] is contraindicated in patients with:
The efficacy of SAGALATIN, is dependent on renal function, and efficacy is reduced in patients who have moderate renal impairment and likely absent in patients with severe renal impairment (see section 4.3). Therefore, SAGALATIN is contraindicated in patients with moderate to severe renal impairment (patients with GFR <60 mL/min) and renal function should be monitored prior to initiation of SAGALATIN and periodically thereafter (see section 4.2).
SAGALATIN is not recommended for patients with severe hepatic impairment. (see section 5.2).
SAGALATIN may cause a decrease in systolic blood pressure and diastolic blood pressure.
Due to its mechanism of action, dapagliflozin as in SAGALATIN, increases diuresis associated with a modest decrease in blood pressure, which may be more pronounced in patients with high blood glucose concentrations.
The diuretic effect of SAGALATIN is a potential concern for volume depleted patients. There is limited data available in patients at increased risk for volume depletion.
For patients at risk for volume depletion to co-existing conditions or concomitant medicines, such as loop diuretics, a 5 mg starting dose of SAGALATIN may be appropriate. SAGALATIN should be permanently discontinued in patients who develop volume depletion (see section 4.8).
Caution should be exercised in patients for whom a drop in blood pressure could pose a risk, such as patients with known cardiovascular disease, patients on antihypertensive therapy with a history of hypotension or elderly patients. For patients receiving SAGALATIN, in case of intercurrent conditions that may lead to volume depletion, careful monitoring of volume status (e.g. physical examination, blood pressure measurements, laboratory tests including haematocrit) and electrolytes is recommended. Temporary interruption of treatment with SAGALATIN is recommended for patients who develop volume depletion until the depletion is corrected (see section 4.8)
SAGALATIN should not be used for the treatment of diabetic ketoacidosis.
There have been post-marketing reports of metabolic acidosis and diabetic ketoacidosis (DKA), including life-threatening and fatal cases, in patients treated with sodium glucose co-transporter 2 (SGLT2) inhibitors, including dapagliflozin, as in SAGALATIN. In a number of cases, the presentation of the condition was atypical with only moderately increased blood glucose values, below 14 mmol/L (250 mg/dL).
It is not known if DKA is more likely to occur with higher doses of dapagliflozin, as in SAGALATIN.
The risk of diabetic ketoacidosis must be considered in the event of non-specific symptoms such as nausea, vomiting, anorexia, abdominal pain, malaise, excessive thirst, difficulty breathing, confusion, unusual fatigue, or sleepiness. Patients should be assessed for ketoacidosis immediately if these symptoms occur, regardless of blood glucose level.
In patients where DKA is suspected or diagnosed, SAGALATIN should be discontinued immediately.
Treatment should be interrupted in patients who are hospitalised for major surgical procedures or acute serious medical illnesses. In both cases, treatment with SAGALATIN may be restarted once the patient’s condition has stabilised.
Before initiating SAGALATIN, factors in the patient history that may predispose to ketoacidosis should be considered.
Patients who may be at higher risk of DKA include patients with a low beta-cell function reserve [e.g. type 2 diabetes patients with low C-peptide or latent autoimmune diabetes in adults (LADA) or patients with a history of pancreatitis or pancreatic surgery], patients with conditions that lead to restricted food intake or severe dehydration, patients for whom insulin doses are reduced and patients with increased insulin requirements due to acute medical illness, surgery or alcohol abuse. SGLT2 inhibitors, including SAGALATIN, is not indicated in these patients.
Restarting SGLT2 inhibitor, including SAGALATIN, treatment in patients with previous DKA while on SGLT2 inhibitor treatment is not recommended, unless another clear precipitating factor is identified and resolved.
SAGALATIN is contraindicated for the treatment of patients with type 1 diabetes mellitus (see section 4.3).
Urinary tract infections may be reported more frequently for SAGALATIN. Urinary glucose excretion may be associated with an increased risk of urinary tract infection; therefore, temporary interruption of SAGALATIN should be considered when treating pyelonephritis or urosepsis (see section 4.8).
Treatment with SAGALATIN increases the risk for urinary tract infections. There have been post-marketing reports of serious urinary tract infections, including pyelonephritis, requiring hospitalisation in patients receiving SAGALATIN and other SGLT2 inhibitors. Evaluate patients for signs and symptoms of urinary tract infections and treat promptly, if indicated.
Insulin and insulin secretagogues, such as sulfonylureas, cause hypoglycaemia. Therefore, a lower dose of insulin or an insulin secretagogue may be required to reduce the risk of hypoglycaemia when used in combination with SAGALATIN (see section 4.8).
Safety and efficacy of SAGALATIN in paediatric patients has not been established.
Elderly patients are more likely to have impaired renal function, and/or to be treated with antihypertensive medicines that may cause changes in renal function, such as angiotensin-converting enzyme inhibitors (ACE-I) and angiotensin II type 1 receptor blockers (ARB). The same recommendations for renal function apply to elderly patients as to all patients (see section 4.2, 4.4, 4.8 and section 5.1).
A higher proportion of patients ≥ 65 years of age treated with dapagliflozin, as in SAGALATIN, may have adverse reactions related to renal impairment or failure. The most frequent adverse reaction related to renal function may be serum creatinine increases, the majority of which may be transient and reversible (see section 4.8).
Elderly patients may be at a greater risk for volume depletion and are more likely to be treated with diuretics. A higher proportion of patients ≥ 65 years of age treated with dapagliflozin, as in SAGALATIN, may have adverse reactions related to volume depletion (see section 4.8).
Therapeutic experience in patients 75 years and older is limited. Initiation of therapy in this population is not recommended (see section 4.2).
Clinical data in patients with New York Heart Association (NYHA) class I – II is limited, and there is no clinical data with dapagliflozin, as in SAGALATIN, in NYHA class III – IV.
While a causal relationship between dapagliflozin, as in SAGALATIN, and bladder cancer is unlikely (see section 4.8), as a precautionary measure, SAGALATIN is not recommended for use in patients concomitantly treated with pioglitazone. Available epidemiological data for pioglitazone suggest a small increased risk of bladder cancer in diabetic patients treated with pioglitazone.
Haematocrit increase may be observed with dapagliflozin, as in SAGALATIN, treatment (see section 4.8); therefore, caution in patients with already elevated haematocrit is warranted.
An increase in cases of lower limb amputation is documented in long-term studies with another SGLT2 inhibitor. It is unknown whether this constitutes a class effect. It is important to counsel patients on routine preventative foot care.
Due to its mechanism of action, patients taking SAGALATIN will test positive for glucose in their urine.
In general, patients with severe renal impairment (eGFR <30 mL/min/1,73 m²) or end stage renal disease or with recent (<2 months), cardiovascular event or heart failure New York Heart Association class IV or who are breastfeeding or are pregnant, have been excluded from clinical studies.
SAGALATIN contains lactose. Patients with rare hereditary conditions of galactose intolerance, e.g. galactosaemia, the Lapp lactase deficiency, or glucose-galactose malabsorption should not take SAGALATIN.
SAGALATIN may add to the diuretic effect of thiazide and loop diuretics and may increase the risk of dehydration and hypotension (see section 4.4).
Insulin and insulin secretagogues, such as sulphonylureas, may cause hypoglycaemia. Therefore, a lower dose of insulin or an insulin secretagogue may be required to reduce the risk of hypoglycaemia when used in combination with dapagliflozin, as in SAGALATIN (see section 4.2 and section 4.8)
The metabolism of dapagliflozin, is primarily mediated by UGT1A9-dependent glucuronide conjugation. The major metabolite, dapagliflozin 3-O-glucuronide, is not an SGLT2 inhibitor.
In in vitro studies, dapagliflozin and dapagliflozin 3-O-glucuronide neither inhibited CYP1A2, 2C9, 2C19, 2D6, 3A4, nor induced CYP1A2, 2B6 or 3A4. Dapagliflozin is a weak substrate of the P-glycoprotein (P-gp) active transporter and dapagliflozin 3-Oglucuronide is a substrate for the OAT3 active transporter. Dapagliflozin or dapagliflozin 3-O-glucuronide did not meaningfully inhibit P-gp, OCT2, OAT1, or OAT3 active transporters.
The dependence of dapagliflozin elimination on dapagliflozin 3-O-glucuronide formation in humans also suggests the possibility of interactions mediated by UGT1A9. Ketoconazole is an in vitro inhibitor of dapagliflozin 3-O-glucuronide formation by UGT1A9 (IC50 = 32 µM).
The pharmacokinetics of SAGALATIN may not be altered by metformin (a human OCT-1 and hOCT-2 substrate), an pioglitazone (a CYP2C8 [major] and CYP3A4 [minor] substrate), sitagliptin (a human OAT-3 substrate and P-glycoprotein substrate), glimepiride (a CYP2C9 substrate), voglibose (an alpha-glucosidase inhibitor), hydrochlorothiazide, bumetanide, valsartan or simvastatin (a CYP3A4 substrate).
Following coadministration of SAGALATIN, with rifampicin (an inducer of various active transporters and medicine metabolising enzymes) a 22% decrease in dapagliflozin systemic exposure (AUC) may be observed, but with no clinically meaningful effect on 24-hour urinary glucose excretion. No dose adjustment is recommended. A clinically relevant effect with other inducers (e.g. carbamazepine, phenytoin, phenobarbitone) is not expected. Following coadministration of SAGALATIN, with mefenamic acid (an inhibitor of UGT1A9), a 55% increase in dapagliflozin systemic exposure may occur, with no clinically meaningful effect on 24-hour urinary glucose excretion. No dose adjustment is recommended.
SAGALATIN may not alter the pharmacokinetics of metformin (a human OCT-1 and hOCT-2 substrate), pioglitazone (a CYP2C8 [major] and CYP3A4 [minor] substrate), sitagliptin (a hOAT 3 substrate and P-glycoprotein substrate), glimepiride (a CYP2C9 substrate), hydrochlorothiazide, bumetanide, valsartan, simvastatin (a CYP3A4 substrate), digoxin (a P-gp substrate) or warfarin (S-warfarin, a CYP2C19 substrate, R-warfarin), or the anticoagulatory effects of warfarin as measured by the prothrombin time [International Normalised Ratio (INR)]. Combination of a single dose of dapagliflozin 20 mg and simvastatin (a CYP3A4 substrate) resulted in a 19% increase in AUC of simvastatin and 31 % increase in AUC of simvastatin acid. The increase in simvastatin and simvastatin acid exposures are not considered clinically relevant.
The effects of smoking, diet, herbal products, and alcohol use on the pharmacokinetics of SAGALATIN have not been studied.
Monitoring glycaemic control with 1,5-AG assay should not be used as measurements of 1,5-AG are unreliable in assessing glycaemic control in patients taking SGLT2 inhibitors, including SAGALATIN. Use alternative methods to monitor glycaemic control.
SAGALATIN is contraindicated in pregnancy. Maternal exposure to SAGALATIN in rat studies is associated with increased incidence and/or severity of renal pelvic and tubular dilatations in progeny. When pregnancy is detected, SAGALATIN should be discontinued (see section 4.3).
Mothers on SAGALATIN should not breastfeed their babies.
SAGALATIN must not be used by a breastfeeding woman. Studies in rats have shown excretion of SAGALATIN in milk. Exposure to SAGALATIN must be avoided during the first 2 years of life (see section 4.3).
The effect of SAGALATIN on fertility in humans has not been studied. In male and female rats, SAGALATIN, showed no effects on fertility at any dose tested.
No studies on the effects on the ability to drive and use machines have been performed. SAGALATIN have no or negligible influence on the ability to drive and use machines. Patients must bear in mind the possibility of hypoglycaemia and its effects on their motor skills.
Frequent: Vulvovaginitis, balanitis and related genital infections, including vulvovaginal mycotic infection, vaginal infection, fungal genital infection, vulvovaginal candidiasis, vulvovaginitis, balanitis candida, genital candidiasis, genital infection, male genital infection, penile infection, vulvitis, bacterial vaginitis, vulval abscess, balanoposthitis, genitourinary tract infection, penile abscess, and posthitis Urinary tract infection, including pyelonephritis, cystitis, Escherichia urinary tract infection, trigonitis, urethritis, kidney infection, and prostatitis.
Less frequent: Fungal infections.
Frequent: Hypoglycaemia (when used with SU or insulin).
Less frequent: Volume depletion, dehydration, hypovolaemia, hypotension, thirst, diabetic ketoacidosis.
Frequent: Dizziness
Less frequent: Constipation, dry mouth
Frequent: Rash, rash generalised, rash pruritic, rash macular, rash maculo-papular, rash pastular, rash vesicular, and rash erythematous.
Less frequent: Hyperhidrosis.
Frequent: Back pain.
Frequent: Glucosuria, dysuria, polyuria, including pollakiuria, increased urine output, and osmotic diuresis.
Less frequent: Nocturia, renal impairment
Less frequent: Vulvovaginal pruritis and pruritus genital.
Frequent: Dyslipidaemia, increased haematocrit, decreased creatinine renal clearance.
Less frequent: Increased blood creatine, increased blood urea
Additional adverse reactions in patients treated with SAGALATIN 10 mg, are described below by treatment regimen:
In patients with moderate renal impairment, a higher frequency of bone fractures may be observed when treated with SAGALATIN (see section 4.3).
A moderate increase in haematocrit occurs and may be an indication of volume depletion.
Frequency unknown: Skin and sub-cutaneous tissue disorders: Rash, generalised rash, pruritic rash, macular rash, maculopapular rash, pustular rash, vesicular rash, erythematous rash.
Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Health care providers are asked to report any suspected adverse reactions to SAHPRA via the “6.04 Adverse Drug Reaction Reporting Form”, found online under SAHPRA’s publications: https://www.sahpra.org.za/Publications/Index/8 or to Cipla by email: drugsafetysa@cipla.com
Not applicable.
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