Proglicem

PACKAGE LEAFLET

Package leaflet: information for the patient

Proglicem 25 mg hard capsules, 100 mg hard capsules

Diazoxide
Please read this leaflet carefully before taking this medicine because it contains
important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any questions, ask your doctor or pharmacist.
• This medicine has been prescribed for you only. Do not give it to others, even if their symptoms are the same as yours, as it could be harmful.
• If you experience any adverse reactions, including those not listed in this leaflet, contact your doctor or pharmacist. See section 4.

Contents of this leaflet:

1. What Proglicem is and what it is used for
2. What you need to know before taking Proglicem
3. How to take Proglicem
4. Possible side effects
5. How to store Proglicem
6. Contents of the pack and other information

1. What Proglicem is and what it is used for

Proglicem contains diazoxide, a substance used for the treatment of hypoglycaemia (low blood sugar levels).
Proglicem is indicated for the treatment of hypoglycaemia of various origins, as its action is primarily due to inhibition of insulin release (the hormone which lowers blood sugar levels).
Proglicem has been shown to be effective in the following conditions:

• if in your child, due to an inherited defect, an amino acid called leucine (a substance used to produce proteins) stimulates the production of insulin hormone, which lowers blood sugar levels (leucine-sensitive idiopathic hypoglycaemia of infancy)
• if a definite cause for your child's low blood sugar level cannot be identified (unclassified idiopathic hypoglycaemia of infancy)
• if you have an inoperable malignant or benign tumour of the pancreas, the gland which produces insulin
• if you have a tumour not involving the pancreas but which nevertheless causes a reduction in blood sugar levels
• if your newborn has low blood sugar levels (neonatal hypoglycaemia)
• if you suffer from glycogen storage disease, an inherited disorder caused by accumulation of glycogen (a sugar reserve) in one or more organs or tissues
• if a definite cause for low blood sugar level cannot be identified (hypoglycaemia of unknown aetiology).

Proglicem may be used before and after surgical removal of the tumour if blood sugar levels remain low.
In cases where other specific medical or surgical treatments prove ineffective or unfeasible, your doctor will consider treatment with Proglicem.

2. What you should know before taking Proglicem

Do not take Proglicem

• if you are allergic to diazoxide or to any of the other ingredients of this medicine (listed in section 6)
• if you have low blood sugar levels due to improper nutrition (functional hypoglycemia)
• if you are allergic to thiazide medicines (medicines used to treat high blood pressure)
• if you are pregnant or breastfeeding. Your doctor will evaluate the benefits the mother may derive from the treatment against the risks of harmful effects on the fetus or newborn.

Warnings and precautions
Talk to your doctor or pharmacist before taking Proglicem.
Your doctor will ask you to undergo regular laboratory tests during treatment to monitor blood levels of white blood cells, platelets, blood and urine sugar levels, and levels of acidic substances (ketone bodies) in the urine.
Periodic blood tests should be performed to detect hematological abnormalities (see section "Possible side effects").
If you experience fluid retention during treatment, your doctor may reduce the dose of Proglicem and prescribe a diuretic medicine, especially if you have heart disease.
After taking Proglicem, you may develop ketoacidosis (when, in the absence of sugar, the body's cells begin to use fatty acids instead of sugar as a source of energy) or hyperosmolar non-ketotic coma (a state of unconsciousness due to cellular dehydration).
Inform your doctor:

• if you suffer from low potassium levels in the blood (hypokalemia).
• if you have severe kidney disease (renal failure). Your doctor may reduce the dose of Proglicem and request laboratory tests to monitor blood electrolyte levels (e.g., sodium and potassium).

Elderly
Specific information on the use of diazoxide in the elderly is not available.
Children and adolescents
Your doctor will monitor your child's growth and bone and mental development during treatment.
In one infant, transient cataract (transient clouding of the lens, the eye's structure responsible for focusing images) occurred together with hyperosmolar coma (a state of unconsciousness due to cellular dehydration). These conditions resolved with correction of the hyperosmolar coma.
Immediately inform your doctor if any of the following conditions occur in a child taking Proglicem:

• abdominal swelling, pain, bloating or discomfort, presence of blood in stools, feeding intolerance (vomiting, poor feeding), drowsiness, as these may be signs of a serious intestinal inflammation (a condition called neonatal necrotizing enterocolitis).

Other medicines and Proglicem
Inform your doctor or pharmacist if you or your child are taking, have recently taken, or might take any other medicines, especially:

• anticoagulant medicines that thin the blood and prevent clot formation (coumarin and its derivatives). Your doctor may reduce the dose of anticoagulant medicines.
• medicines for high blood pressure such as thiazides and other diuretics, as co-administration with Proglicem may increase the effects of these medicines and of Proglicem. Your doctor may prescribe insulin or tolbutamide to treat hyperglycemia (high blood sugar levels) caused by Proglicem.
• phenytoin, a medicine used to treat epilepsy, as co-administration with Proglicem may reduce the effect of this medicine.
• alpha-blocking medicines used to treat high blood pressure or benign enlargement of the prostate (benign prostatic hyperplasia), a gland in men that produces seminal fluid.

Inform your doctor:

• if you or your newborn suffers from high levels of bilirubin in the blood, a yellow-red pigment found in bile (hyperbilirubinemia).
• if you suffer from low potassium levels in the blood (hypokalemia).

Proglicem may alter the results of certain laboratory tests (blood glucose and uric acid levels).
Proglicem and food
For information on taking Proglicem with food, see section 3 "How to take Proglicem".
Pregnancy, breastfeeding and fertility
If you are pregnant, suspect you may be pregnant, plan to become pregnant, or are breastfeeding, ask your doctor or pharmacist for advice before taking this medicine.
Like other medicines, Proglicem must not be administered during pregnancy or breastfeeding.
Your doctor will evaluate the benefits the mother may derive from the treatment against the risks of harmful effects on the fetus and newborn.
There are no data regarding the passage of diazoxide into breast milk. Since many medicines pass into breast milk and considering the possibility of adverse effects of diazoxide in newborns, your doctor will decide whether to discontinue breastfeeding or the medicinal treatment, taking into account the importance of the medicine for the mother.
Driving and using machines
Proglicem impairs the ability to drive vehicles or operate machinery.
If you experience a drop in blood pressure upon changing from a sitting to a standing position (postural hypotension) or drowsiness, consider the risks associated with driving vehicles or operating machinery.
Proglicem contains lactose
If your doctor has diagnosed you with an intolerance to certain sugars, contact them before taking this medicine.

3. How to take Proglicem

Take this medicine exactly as directed by your doctor or pharmacist. If you
have any doubts, consult your doctor or pharmacist.
Proglicem should, as far as possible, be administered after meals.
The dosage of the medicine must be determined according to the patient's clinical condition and response to
treatment.
During the first days of treatment with Proglicem, blood glucose levels should be monitored regularly.
Adults and adolescents
The recommended dose is 3–8 mg/kg, given in 2–3 divided doses.
The recommended initial dose is 3 mg/kg per day, divided into two or three doses over 24 hours, to
assess your response to the medicine. Your doctor may then decide to increase the dose so that symptoms and blood glucose levels respond satisfactorily. In patients with benign or malignant pancreatic tumours producing large amounts of insulin, doses up to 1,000 mg per day have been used exceptionally.
Proglicem should, as far as possible, be administered after meals.
The duration of treatment with Proglicem varies depending on the indication, and in cases of malignant tumours causing low blood sugar levels (hypoglycaemia), treatment may continue indefinitely.
Use in children and neonates
The recommended dose in children with leucine-sensitive hypoglycaemia (a condition in which an amino acid
called leucine, a substance used to produce proteins, due to an inherited defect, stimulates the production of the hormone insulin, thereby lowering blood sugar levels) is 8–15 mg/kg per day, divided into two or three doses, starting at 8 mg/kg per day.
Hypoglycaemia in paediatric patients may resolve spontaneously, although the age at which this occurs cannot be predicted. Your doctor will arrange regular hospital admissions at intervals to attempt to reduce the dose of diazoxide and to facilitate therapy.
If there is no therapeutic response within 2–3 weeks, your doctor will instruct you to discontinue
taking Proglicem.
If you take more Proglicem than you should
In case of accidental ingestion/overdose of Proglicem, contact your doctor immediately or go to the nearest hospital.
Symptoms
Increased blood sugar levels (hyperglycaemia) or sugar in the urine (glycosuria), which may require a dose reduction.
Treatment
Administration of insulin and rehydration solutions is recommended. Peritoneal dialysis and haemodialysis (blood purification procedures) have been shown to reduce diazoxide blood levels.
Following accidental ingestion/overdose of Proglicem, your doctor will keep you under close observation for 7 days.
If you forget to take Proglicem
Do not take a double dose to make up for the missed dose.
If you stop taking Proglicem
If you have any questions about using this medicine, consult your doctor or pharmacist.
If there is no therapeutic response within 2–3 weeks, the medicine should be discontinued.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Common and serious side effects
Fluid and salt retention, which usually responds to treatment with diuretic medicines (medicines used to treat high blood pressure). This retention is more frequent in adults and may lead to a serious heart condition (congestive heart failure) in patients with impaired cardiac reserve (impaired ability of the heart to increase the volume of blood it pumps out).

Serious side effects with unknown frequency
These may develop very rapidly:

• Diabetic ketoacidosis (a condition occurring in patients with diabetes when, in the absence of sugars, the body's cells start using fatty acids instead of sugars as an energy source);
• Non-ketotic hyperosmolar coma (a state of unconsciousness due to cellular dehydration).

Other common side effects
In women, hirsutism may occur, i.e. growth of fine, downy hair on the upper face, back, and limbs. This usually regresses after discontinuation of treatment. The occurrence of hirsutism should not lead to discontinuation of therapy when the therapeutic effects of the medicine are life-saving.

Common:

• Loss or reduction of appetite (anorexia),
• nausea,
• vomiting,
• abdominal pain,
• transient loss of taste,
• increased heart rate (tachycardia),
• sensation of increased heartbeats (palpitations),
• low blood pressure (hypotension), which may be enhanced when administered together with medicines used to treat high blood pressure (such as thiazide diuretics),
• hyperuricaemia (elevated levels of uric acid in the blood), usually asymptomatic,
• reduced platelet count, a type of blood cell (thrombocytopenia), with or without purpura (skin spots of variable size and colour ranging from bright red, to purple, to reddish-brown), which usually requires discontinuation of therapy (see section “Warnings and precautions”),
• decrease in a type of white blood cells (neutropenia), usually transient,
• dizziness,
• movement disorders (extrapyramidal symptoms),
• headache,
• weakness,
• visual disturbances (visual disturbances),
• increased levels of sugar in blood and urine, requiring dose reduction to avoid progression to a condition in which, due to lack of sugars, the body's cells start using fatty acids as an energy source (diabetic ketoacidosis), and to a state of unconsciousness due to cellular dehydration (hyperosmolar coma) (see section “If you take more Proglicem than you should”).

Uncommon:

• diarrhoea.

Rare:

• intestinal blockage (ileus),
• chest pain,
• acute inflammation of the pancreas (acute pancreatitis).

Frequency not known:

• transient increase in blood pressure (transient hypertension),
• increase in a type of white blood cells (eosinophilia),
• reduction in the percentage of red blood cells in the blood (haematocrit)/reduction in a blood protein (haemoglobin),
• excessive bleeding,
• decrease in a type of antibodies (proteins involved in the body's defence mechanisms),
• increase or decrease in laboratory test values of certain parameters related to liver and kidney function (increase in SGOT, alkaline phosphatase, and blood urea nitrogen; decrease in creatinine clearance),
• reversible kidney disease (reversible nephrotic syndrome),
• reduced urine output (urination),
• presence of blood in the urine (haematuria),
• presence of albumin, a protein produced by the liver, in the urine (albuminuria),
• anxiety,
• insomnia,
• inflammation of nerves (polyneuritis),
• sensation of numbness (paraesthesia),
• itching (pruritus),
• malaise,
• somnolence,
• transient cataract (clouding of the lens of the eye, which focuses images),
• presence of blood in the eyes (subconjunctival haemorrhage),
• partial blindness (ring scotoma),
• double vision (diplopia),
• tearing,
• a skin infection (cutaneous candidiasis),
• rash,
• herpes,
• premature ageing of bones,
• hair loss,
• fever,
• swelling of lymph nodes, small glands located along the lymphatic vessels (lymphadenopathy),
• a metabolic disorder characterized by attacks of pain, redness, and swelling of the joints (gout),
• premature death of pancreatic tissue (pancreatic necrosis),
• milk discharge from the breasts (galactorrhoea),
• enlargement of breast nodules,
• breast enlargement (gynaecomastia),
• a severe reaction to the medicine affecting the skin, blood, and internal organs, called DRESS.

Pericardial effusion (fluid around the heart) has been reported.
The following side effects have also been reported, although the patient's condition sometimes made it difficult to determine which side effect was caused by the medicine:

Common:

• skin reactions (drug rash, photosensitivity).

Frequency not known:

• defective bone tissue formation (osteodystrophy),
• increased heart size (cardiomegaly).

Side effects in children and adolescents
Common and serious side effects
Fluid and salt retention, which usually responds to treatment with diuretic medicines (medicines used to treat high blood pressure). This retention is more frequent in young children (neonates) and may lead to a serious heart condition (congestive heart failure) in patients with impaired cardiac reserve (impaired ability of the heart to increase the volume of blood it pumps out).

Other common side effects
Hirsutism may occur in children, i.e. growth of fine, downy hair on the upper face, back, and limbs, which usually regresses after discontinuation of the medicine.

Other side effects
Pulmonary arterial hypertension (high blood pressure in the lungs) has also been observed in infants, neonates, and children; in most reported cases, pulmonary hypertension improved after discontinuation of Proglicem treatment.
Other side effects with unknown frequency: necrotizing enterocolitis in neonates (inflammation of the intestine with blood in the stool and tissue death).

Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, talk to your doctor or pharmacist. You may also report side effects directly via the national reporting system at: https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse.
By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Proglicem

Do not store above 25 °C.
Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the pack after Exp.
The expiry date refers to the last day of that month.
Do not dispose of any medicine via wastewater or household waste. Ask your pharmacist how to
dispose of medicines you no longer use. This will help protect the environment.

6. Package contents and other information

What Proglicem contains

• The active substance is diazoxide. Proglicem 100 mg hard capsules: each capsule contains 100 mg of diazoxide. Proglicem 25 mg hard capsules: each capsule contains 25 mg of diazoxide.
• The other components are:
  • Proglicem 25 mg: lactose, magnesium stearate. Composition of the capsule shell: gelatin, purified water.
  • Proglicem 100 mg: lactose, magnesium stearate. Composition of the capsule: gelatin, titanium dioxide (E171).

Description of the appearance of Proglicem and contents of the pack
Proglicem is presented as capsules.
It is available in:

• Box containing 100 capsules of 25 mg in blisters
• Box containing 100 capsules of 100 mg in blisters.

Marketing Authorization Holder and Manufacturer
Marketing Authorization Holder
MSD Italia S.r.l., Via Vitorchiano, 151 – 00189 Rome, Italy
Manufacturer
Merck Sharp & Dohme B.V., Waarderweg 39, 2031 BN, Haarlem – The Netherlands