Consumer medicine information

Sozol

Pantoprazole

BRAND INFORMATION

Brand name

Sozol

Active ingredient

Pantoprazole

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Sozol.

What is in this leaflet?

This leaflet answers some common questions about SOZOL. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking SOZOL against the benefits they expect it will have for you. Use SOZOL as directed and follow the advice given in this leaflet.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

What SOZOL is used for

The name of your medicine is SOZOL. It contains the active ingredient called pantoprazole.

Ulcers
SOZOL is used to treat and help heal duodenal and gastric ulcers. Depending on the position of the ulcer it is called a gastric or duodenal ulcer. A gastric ulcer occurs in the stomach. A duodenal ulcer occurs in the duodenum, which is the tube leading out of the stomach.

These can be caused in part by too much acid being made in the stomach.

SOZOL may also be used to prevent ulcers associated with the use of non-steroidal anti-inflammatory drugs (NSAIDs). These are medicines used to relieve pain, swelling and other symptoms of inflammation, including arthritis (inflammation of the joints).

Reflux disease
SOZOL is also used to treat reflux oesophagitis or reflux disease. This can be caused by "washing back" (reflux) of food and acid from the stomach into the food pipe, also known as the oesophagus. Reflux can cause a burning sensation in the chest rising up to the throat, also known as heartburn.

SOZOL is also used to prevent reflux oesophagitis from coming back.

Zollinger-Ellison syndrome
SOZOL is used to treat a rare condition called Zollinger-Ellison syndrome, where the stomach produces very large amounts of acid, much more than in ulcers and reflux disease.

Other uses
Your doctor may have prescribed SOZOL for another reason. Ask your doctor if you have any questions about why SOZOL has been prescribed for you.

This medicine is not addictive. This medicine is available only with a doctors’s prescription. This medicine is not expected to affect your ability to drive a car or operate machinery.

However, do not drive a car or operate machines if you experience side effects such as dizziness or blurred vision.

SOZOL should not be given to children under 5 years of age. There is not enough information to recommend the use of this medicine for children under the age of 5 years.

How SOZOL works

SOZOL belongs to a group of medicines called proton pump inhibitors (PPls). SOZOL works by decreasing the amount of acid the stomach makes, to give relief from the symptoms and allow healing to take place.

There is no evidence that SOZOL is addictive. This medicine is available only with a doctor's prescription.

Before you start to take SOZOL

When you must not take it

Do not take SOZOL if you have an allergy to:

  • Any medicine containing pantoprazole
  • any of the ingredients listed at the end of this leaflet.

Some symptoms of an allergic reaction include skin rash, itching, shortness of breath or swelling of the face, lips or tongue, which may cause difficulty in swallowing or breathing.

Do not take SOZOL if you have severe liver disease or cirrhosis.

Do not take SOZOL in combination with antibiotics or any other medicine if:

  • you are allergic to any of the antibiotics or medicines your doctor may prescribe with SOZOL.
  • you have moderate to severe liver or kidney disease.

Do not take SOZOL in combination with atazanavir or nelfinavir (an anti-viral medication).

SOZOL should not be given to children. The safety and effectiveness of SOZOL in children have not been established.

If you are not sure whether you should start taking SOZOL alone or SOZOL in combination with antibiotics, talk to your doctor.

Do not take SOZOL after the expiry date (EXP) printed on the pack, or if the packaging is torn or shows signs of tampering. If it has expired or is damaged, return it to your pharmacist for disposal.

Before you start to take it

You must tell your doctor if:

  1. you have any allergies to:
  • pantoprazole
  • any of the ingredients listed at the end of this leaflet
  • any other medicines, or any other substances, such as foods, preservatives or dyes.
  1. you are pregnant, intend to become pregnant, are breastfeeding or intend to breastfeed. Your doctor will discuss the risks and benefits of taking SOZOL during pregnancy or while breast-feeding.
  2. you have or have had any other medical conditions.

If you have not told your doctor about any of the above, tell them before you take SOZOL.

Tell your doctor if you have any of the following symptoms:

  • Unintentional weight loss
  • Repeated vomiting
  • Vomiting blood
  • Difficulty or pain when swallowing
  • You look pale and feel weak
  • You notice blood in your stools

Your doctor may need to perform some additional tests before you take SOZOL.

Taking other medicines

Tell your doctor if you are taking any other medicines, including medicines that you buy without a prescription from your pharmacy, supermarket, or health food shop.

Some medicines and Sozol may interfere with each other. These include:

  • Warfarin, phenprocoumon-medicines used to prevent blood clots (anticoagulants)
  • Atazanavir, nelfinavir – medicines used to treat viral infections such as HIV
  • Ketoconazole, itraconazole, posaconazole – medicines used to treat fungal infection
  • Methotrexate – a medicine used to treat arthritis and some types of cancer
  • Erlotinib or related medicines used to treat cancer
  • Tacrolimus, mycophenolate mofetil – medicines used to suppress the immune system
  • Fluvoxamine – a medicine used to treat anxiety and depression

These medicines may be affected by SOZOL, or may affect how well it works. You may need to use different amounts of your medicine, or take different medicines.

Your doctor or pharmacist has more information on medicines to be careful with or to avoid while taking SOZOL.

How to take SOZOL

How much to take

The usual dose is one tablet per day.

In children over 5 years of age, the dose of SOZOL for reflux oesophagitis or reflux disease is based on weight and may be 20 mg or 40 mg, depending on the condition being treated. Sozol should not be taken for longer than 8 weeks.

Your doctor will prescribe the dose that is right for you. The dose and frequency of SOZOL that your doctor prescribes for you depends on your medical condition. Your doctor may change the dose as your condition changes.

How and when to take it

Swallow your tablets whole with a little water, with or without food.

Take SOZOLat about the same time each day. Taking it at the same time each day will have the best effect. It will also help you remember when to take it.

Do not crush or chew the tablets. SOZOL tablets have a special coating to protect them from the acidic contents of your stomach. For SOZOL to work effectively, this coating must not be broken.

How long to take it

Continue taking your medicine for as long as your doctor tells you.

If you forget to take it

If it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to. Otherwise, take it as soon as you remember, and then go back to taking it as you would normally.

Do not take a double dose to make up for the dose that you missed. This may increase the chance of you getting an unwanted side effect.

If you are not sure what to do, ask your doctor or pharmacist. If you have trouble remembering to take your medicine, ask your pharmacist for some hints.

If you take too much (overdose)

Immediately telephone your doctor or Poisons Information Centre for advice (Ph: 13 11 26) or go to Accident and Emergency (Casualty) at your nearest hospital, if you think that you or anyone else may have taken too much SOZOL. Do this even if there are no signs of discomfort or poisoning. Urgent medical attention may be needed. Keep telephone numbers for these places handy.

While you are taking SOZOL

Things you must do

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking SOZOL.

Tell any other doctors, dentists and pharmacists who treat you that you are taking this medicine.

If you are going to have surgery, tell the surgeon that you are taking this medicine.

If you become pregnant while you are taking this medicine, tell your doctor or pharmacist immediately.

If you are about to have any blood tests, tell your doctor that you are taking this medicine. It may interfere with the results of some tests.

Keep all of your doctors’ appointments so that your progress can be checked. Your doctor may do some tests from time to time to make sure the medicine is working and to prevent unwanted side effects.

Things you must not do

Do not give SOZOL to anyone else, even if they have the same symptoms as you.

Do not use SOZOL to treat any other complaints unless your doctor tells you to.

Things that may help your condition

Some self-help measures suggested below may help your condition. Talk to your doctor or pharmacist about these measures and for more information.

  • Alcohol: your doctor may advise you to limit your alcohol intake.
  • Aspirin and many other medicines used to treat arthritis, period pain, headaches: these medicines may irritate the stomach and may make your condition worse. Your doctor or pharmacist may suggest other medicines you can take.
  • Caffeine: your doctor may advise you to limit the number of drinks which contain caffeine, such as coffee, tea, cocoa and cola drinks, because they contain ingredients that may irritate your stomach.
  • Eating habits: eat smaller, more frequent meals. Eat slowly and chew your food carefully. Try not to rush at meal times.
  • Smoking: your doctor may advise you to stop smoking or at least cut down.
  • Weight: your doctor may suggest losing some weight to help your condition.

Side effects

Tell your doctor as soon as possible if you have any problems while taking SOZOL, even if you do not think the problems are connected with the medicine or they are not listed in this leaflet.

Like other medicines, SOZOL can cause some side effects. If they occur, most are likely to be minor and temporary. However, some may be serious and need medical attention.

Ask your doctor or pharmacist any questions you may have. Tell your doctor if you notice any of the following and they worry you:

  • headache
  • dizziness
  • diarrhoea
  • nausea or vomiting
  • stomach pain
  • excessive gas in the stomach or bowel
  • indigestion
  • constipation
  • dry mouth
  • metallic taste
  • weakness or tiredness
  • increased sweating or body temperature
  • blurred vision
  • skin problems such as itchiness and rash
  • trouble sleeping

These are the more common side effects of SOZOL. Some of these side effects may be due to the combination of other medicines you are taking with SOZOL.

Tell your doctor immediately if you notice any of the following:

  • unusual tiredness or weakness
  • nausea, vomiting, loss of appetite, feeling generally unwell, fever, itching, yellowing of the skin and eyes, and dark-coloured urine
  • blood in the urine
  • increased or decreased need to urinate
  • skin problems such as itchiness and rash, or swelling, blistering or peeling of the skin or rash when exposed to the sun, possibly with pain in the joints.
  • swelling of the face, lips, mouth, tongue or throat which may cause difficulty in swallowing or breathing
  • frequent infections such as fever, severe chills, sore throat or mouth ulcers
  • chest pain
  • shortness of breath
  • high blood pressure
  • water retention, swelling
  • swelling of the legs
  • bleeding or bruising more easily than normal
  • depression, confusion or anxiety
  • bone fracture of the hip, wrist or spine (mainly a risk in people who take high doses of PPIs or use them long term ( a year or longer))
  • symptoms such as seizures, abnormal or fast heartbeat or jerking/shaking movements. These can be a sign of low magnesium, calcium or potassium levels in your blood
  • severe and/or persistent diarrhoea, because this medicine has been associated with a small increase in infectious diarrhoea.

These may be serious side effects and you may need urgent medical attention. Serious side effects are rare. Other side effects not listed above may occur in some people.

Tell your doctor if you notice anything that is making you feel unwell when you are taking, or soon after you have finished taking SOZOL. Ask your doctor or pharmacist if you do not understand some of the information in this list.

Do not be alarmed by this list of possible side effects. You may not experience any of them.

After taking SOZOL

Storage

Keep your tablets in their blister pack until it is time to take them. If you take the tablets out of the blister pack they may not keep well.

Keep SOZOL tablets in a cool dry place where the temperature stays below 25°C.

Do not store SOZOL or any other medicines in a bathroom or near a sink. Do not leave it in the car or on window sills. Heat and dampness can destroy some medicines.

Keep SOZOL where children cannot reach it. A locked cupboard at least one-and- a-half metres above the ground, is a good place to store medicines.

Disposal

If your doctor tells you to stop taking SOZOL or the tablets have passed their expiry date, ask your pharmacist what to do with any tablets that are left over.

Product description

What it looks like

SOZOL is available as 20 mg and 40 mg tablets. The tablets have an acid-resistant coating called an enteric coating.

The 20 mg tablets are yellow to pale yellow, oval shaped, and plain on both sides. The 40 mg tablets are yellow to pale yellow, oval shaped, and plain on both sides.

SOZOL 20 mg tablets are available in blister packs of 30 tablets.

SOZOL 40 mg tablets are available in blister packs of 30 tablets.

Ingredients

The active ingredient in SOZOL tablets is pantoprazole. SOZOL 20 mg tablets contain the equivalent of 20 mg pantoprazole (as sodium sesquihydrate), and SOZOL 40 mg tablets contain the equivalent of 40 mg pantoprazole (as sodium sesquihydrate).

SOZOL tablets also contain mannitol, sodium carbonate, sodium starch glycollate, crospovidone, colloidal anhydrous silica, calcium stearate, hypromellose, macrogol 6000, sodium hydroxide, EUDRAGIT L30-D55 (ARTG No 3700) and OPADRY AMB Aqueous Moisture Barrier Coating System 80W52172 Yellow (ARTG No 106688).

SOZOL tablets do not contain gluten, lactose, sucrose, tartrazine or other azo dyes.

Sponsor:

Arrow Pharma Pty Ltd
15-17 Chapel Street,
Cremorne, VIC 3121
Australia

Australian Registration Numbers

SOZOL 20 mg – AUST R 191034

SOZOL 40 mg – AUST R 191035

This leaflet was last updated in September 2020.

Published by MIMS October 2020

BRAND INFORMATION

Brand name

Sozol

Active ingredient

Pantoprazole

Schedule

S4

 

1 Name of Medicine

Pantoprazole sodium (as pantoprazole sodium sesquihydrate).

2 Qualitative and Quantitative Composition

Each Sozol 20 mg enteric coated tablet contains 22.7 mg pantoprazole sodium sesquihydrate equivalent to 20 mg of pantoprazole.
Each Sozol 40 mg enteric coated tablet contains 45.4 mg of pantoprazole sodium sesquihydrate equivalent to 40 mg of pantoprazole.

Excipients of known effect.

Lactose monohydrate and saccharin.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Sozol is available as 20 mg (yellow to pale yellow, oval shaped, plain on both sides) and 40 mg (yellow to pale yellow, oval shaped, plain on both sides) biconvex, enteric-coated tablets.

4 Clinical Particulars

4.1 Therapeutic Indications

1. For symptomatic improvement and healing of the following gastrointestinal diseases which require a reduction in acid secretion:
Duodenal ulcer.
Gastric ulcer.
Gastro-oesophageal reflux disease (GORD): i. symptomatic GORD. The treatment of heartburn and other symptoms with GORD; ii. reflux oesophagitis.
Gastrointestinal lesions refractory to H2-blockers.
Zollinger-Ellison syndrome.
Patients whose gastric or duodenal ulceration is not associated with ingestion of non-steroidal anti-inflammatory drugs (NSAIDs) require treatment with antimicrobial agents in addition to antisecretory drugs whether on first presentation or on recurrence.
2. Maintenance of healed reflux oesophagitis in patients previously treated for moderate to severe reflux oesophagitis.
3. Prevention of gastroduodenal lesions and dyspeptic symptoms associated with non-selective non-steroidal anti-inflammatory drugs (NSAIDs) in increased risk patients with a need for continuous non-selective NSAID treatment.

4.2 Dose and Method of Administration

Adults.

Sozol tablets should not be chewed or crushed but swallowed whole with a little water.

Duodenal ulcer.

Sozol 40 mg (one tablet) should be given once a day. In most patients freedom from symptoms is achieved rapidly and healing generally occurs within two weeks. If a two-week period of treatment is not sufficient, healing will be achieved in almost all cases within a further two weeks.

Gastric ulcer.

Sozol 40 mg (one tablet) should be given once a day. In most patients freedom from symptoms is achieved rapidly and healing usually takes four weeks. If a four-week period of treatment is not sufficient, healing will usually be achieved in a further four weeks.

Lesions refractory to H2-receptor antagonists.

Sozol 40 mg (one tablet) should be given once a day. In most patients freedom from symptoms is achieved rapidly and healing usually takes four weeks. If a four-week period of treatment is not sufficient, healing is achieved in the majority of patients in a further four weeks. In a small group of patients, there may be benefit in extending pantoprazole therapy to a total of 12 weeks.

Zollinger-Ellison syndrome.

The number of Sozol 40 mg tablets should be individually adjusted so that the acid output remains below 10 mmol/L. No fixed period of time is proposed for treatment of Zollinger-Ellison syndrome.

Gastroesphageal reflux disease (GORD).

Symptomatic GORD (treatment of symptomatic reflux).

The recommended dosage is one Sozol 20 mg tablet per day. If symptom control has not been achieved after four weeks treatment with Sozol 20 mg tablets daily, further investigation is recommended, for example, endoscopy.

Treatment of reflux oesophagitis.

The recommended oral dosage is one Sozol 20 or 40 mg tablet/day. A four-week period is usually required for healing, however if this is not sufficient, healing will usually be achieved within a further four weeks. This dosage may be increased up to pantoprazole 80 mg/day.

Maintenance of healed reflux oesophagitis in patients previously treated for moderate to severe reflux oesophagitis.

For long-term management, a maintenance dose of one Sozol 20 or 40 mg tablet/day is recommended, dependent upon patient response.

Prevention of gastroduodenal lesions and dyspeptic symptoms associated with nonselective NSAIDs in increased risk patients with a need for continuous nonselective NSAID treatment.

The recommended oral dosage is one Sozol 20 mg tablet per day.

Infants and children.

There is insufficient experience in children under 5 to justify a general recommendation.

Use in the elderly.

The usual daily dosage of 20 or 40 mg can be given.

Renal insufficiency.

The usual daily dose of 20 or 40 mg can be given.

Hepatic insufficiency.

Pantoprazole is contraindicated in patients with cirrhosis or severe liver disease (see Section 4.3 Contraindications). With milder forms of liver disease, the minimum effective dose has not been determined and the initial dose should be reduced.

Monitoring advice.

In long-term treatment, especially when exceeding a treatment period of 1 year, patients should be kept under regular surveillance.
Patients being treated for symptomatic GORD with Sozol 20 mg who do not respond after 4 weeks should be investigated.

4.3 Contraindications

Known hypersensitivity to pantoprazole, substituted benzimidazoles or any other components of the formulation or in cases of cirrhosis or severe liver disease.
Combination therapy for eradication of H. pylori is contraindicated in patients with known hypersensitivity to any of the antibiotics proposed for combination therapy for eradication of H. pylori or in patients with moderate to severe hepatic or renal dysfunction. The product information for the individual components of the combination H. pylori eradication therapy should be consulted for any further contraindications.
Pantoprazole, like other proton pump inhibitors, should not be co-administered with HIV protease inhibitors, such as atazanavir or nelfinavir (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

4.4 Special Warnings and Precautions for Use

Check the following before use.

In the case of combination therapy for the eradication of H. pylori, the product information for the antibiotics used in the combination should be observed.
In the presence of any alarm symptoms (e.g. significant unintentional weight loss, recurrent vomiting, dysphagia, haematemesis, anaemia or melaena) and when gastric ulcer is suspected or present, malignancy should be excluded, as treatment with pantoprazole may alleviate symptoms and delay diagnosis. Further investigation is to be considered if symptoms persist despite adequate treatment.

Clostridium difficile.

PPI therapy may be associated with an increased risk of Clostridium difficile infection.
Pantoprazole, like all proton pump inhibitors, might be expected to increase the counts of bacteria normally present in the upper gastrointestinal tract. Treatment with pantoprazole may lead to a slightly increased risk of gastrointestinal infections caused by bacteria such as Salmonella, Campylobacter and Clostridium difficile.

Influence on vitamin B12 absorption.

Pantoprazole, as all acid blocking medicines, may reduce the absorption of cyanocobalamin (vitamin B12) due to hypochlorhydria or achlorhydria. This should be considered in patients with reduced body stores or risk factors for reduced vitamin B12 absorption (such as the elderly) on long-term therapy and in patients with Zollinger-Ellison syndrome and other pathological hypersecretory conditions requiring long-term treatment if respective clinical symptoms are observed. Rare cases of cyanocobalamin (vitamin B12) deficiency following acid blocking therapy have been reported.

Non-steroidal anti-inflammatory drugs.

Use of Sozol 20 mg for prevention of gastroduodenal lesions and dyspeptic symptoms associated with non-selective NSAIDs should be restricted to patients who require continued non-selective NSAID treatment and have an increased risk of developing gastrointestinal complications. The increased risk should be assessed according to individual risk factors, e.g. high age (> 65 years), history of gastric or duodenal ulcer or upper gastrointestinal bleeding.

Subacute cutaneous lupus erythematosus (SCLE).

Proton pump inhibitors are associated in rare cases with the occurrence of subacute cutaneous lupus erythematosus (SCLE). If lesions occur, especially in sun exposed areas of the skin, and if accompanied by arthralgia, the patient should seek medical help promptly and the healthcare professional should consider stopping the product.

Bone fracture.

PPI therapy may be associated with an increased risk for osteoporosis-related fractures of the hip, wrist, or spine. The risk of fracture was increased in patients who received high-doses; defined as multiple daily doses, and long-term PPI therapy (a year or longer).

Acute interstitial nephritis.

Acute interstitial nephritis has been observed in patients taking PPIs including pantoprazole. Acute interstitial nephritis may occur at any point during PPI therapy and is generally associated to an idiopathic hypersensitivity reaction. Discontinue pantoprazole if acute interstitial nephritis develops.

Hypomagnesaemia.

Hypomagnesaemia has been rarely reported in patients treated with PPIs for at least three months (in most cases after a year of therapy). Serious consequences of hypomagnesaemia include tetany, arrhythmia, and seizure. Hypomagnesaemia may lead to hypocalcaemia and/or hypokalaemia (see Section 4.8 Adverse Effects (Undesirable Effects)).

General toxicity.

Gastrointestinal system.

Treatment with pantoprazole causes dose-dependent hypergastrinaemia as a result of inhibition of gastric acid secretion. Gastrin has a trophic effect on the gastric mucosa, and increases in gastric weight have been observed in rats and dogs to be dependent upon both dose and duration of treatment. Accompanying histopathological changes in the gastric mucosa were increased height, dilatation of fundic glands, chief cell hyperplasia and/or atrophy and parietal cell hyperplasia or vacuolation/degeneration. Increased density of enterochromaffin-like (ECL) cells was observed after 12 months treatment at dose levels from 5 mg/kg/day in rats and 2.5 mg/kg/day in dogs; all changes were reversible after various recovery periods. Since these gastric effects are a consequence of the pharmacological effect of acid secretion inhibition, no-effect doses were not established in all instances.
Although rats might be more susceptible to this effect than other species because of their high ECL cell density and sensitivity to gastrin, ECL cell hyperplasia occurs in other species, including mice and dogs, and has been observed in one of two clinical trials in which ECL cell density was measured (a 2-fold increase was observed in study RR126/97 after up to 5 years of treatment with regular and high doses, but no increase was observed in study RR125/97). No dysplasic or neoplastic changes were observed in gastric endocrine cells in either study.

Ocular toxicity and dermal phototoxicity/sensitivity.

Studies have shown that pantoprazole is retained in low levels in the eyes and skin of pigmented rats. It is likely that the retention reflects a reversible association with melanin. Animal studies investigating the potential for phototoxicity/photosensitivity have not been conducted. A 2-week dog study, conducted specifically to investigate the effects on the eye and ear, did not reveal any changes relating to pantoprazole treatment, but the doses chosen were relatively low (with exposures (AUC) of 0.2- to 10-fold (oral) and 1- to 2-fold (IV) the clinical exposure). No ophthalmological changes or changes in electroretinographs were observed in cynomolgus monkeys at IV doses of up to 15 mg/kg/day for 4 weeks.

Monitoring.

In long-term treatment, especially when exceeding a treatment period of one year, patients should be kept under regular surveillance.
Patients being treated for symptomatic GORD with Sozol 20 mg who do not respond after four weeks should be investigated.

Use in hepatic impairment.

See Section 4.2 Dose and Method of Administration, Hepatic insufficiency; Section 5.2 Pharmacokinetic Properties, Special populations.

Use in renal impairment.

See Section 4.2 Dose and Method of Administration, Renal insufficiency; Section 5.2 Pharmacokinetic Properties, Special populations.

Use in the elderly.

See Section 4.2 Dose and Method of Administration, Use in the elderly; Section 4.4 Special Warnings and Precautions for Use, Influence on vitamin B12 absorption; Section 5.2 Pharmacokinetic Properties, Special populations.

Paediatric use.

To date there is insufficient experience with treatment in children under 5 to justify a general recommendation.

Effects on laboratory tests.

Increased Chromogranin A (CgA) level may interfere with investigations for neuroendocrine tumours. To avoid this interference, proton pump inhibitor treatment should be stopped 14 days before CgA measurements.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Pantoprazole is metabolised in the liver via the cytochrome P450 enzyme system. A study using human liver microsomes suggested that the P450 enzymes CYP2C19 and CYP3A4 are involved in its metabolism. In addition, CYP2D6 and CYP2C9-10 were implicated in another study. An interaction of pantoprazole with other drugs or compounds which are metabolised using the same enzyme system cannot be excluded. However, no clinically significant interactions were observed in specific tests with a number of such drugs or compounds, namely carbamazepine, caffeine, diazepam, diclofenac, digoxin, ethanol, glibenclamide, metoprolol, naproxen, nifedipine, phenytoin, piroxicam, theophylline and the low dose oral contraceptive Triphasil (levonorgestrel and ethinyloestradiol). There was also no interaction with a concomitantly administered antacid (aluminium hydroxide and magnesium hydroxide).
Treatment of dogs with IV famotidine shortened the duration of the pH elevation effect of pantoprazole.
Four crossover pharmacokinetic studies designed to examine any interactions between pantoprazole and the drugs clarithromycin, amoxycillin and metronidazole, conducted in 66 healthy volunteers, showed no interactions.

Drugs with pH-dependent absorption pharmacokinetics.

As with all acid suppressant medications, the absorption of drugs whose bioavailability is pH dependent (e.g. ketoconazole, itraconazole, posaconazole, erlotinib), might be altered due to the decrease in gastric acidity.

HIV protease inhibitors.

It has been shown that coadministration of atazanavir 300 mg/ritonavir 100 mg with omeprazole (40 mg once daily) or atazanavir 400 mg with lansoprazole (60 mg single dose) to healthy volunteers resulted in a substantial reduction in the bioavailability of atazanavir. The absorption of atazanavir is pH dependent. Therefore, proton pump inhibitors, including pantoprazole, should not be coadministered with HIV protease inhibitors for which absorption is dependent on acidic intragastric pH, such as atazanavir or nelfinavir (see Section 4.3 Contraindications).

Mycophenolate mofetil.

Co-administration of PPIs in healthy subjects and in transplant patients receiving mycophenolate mofetil has been reported to reduce the exposure to the active metabolite, mycophenolic acid. This is possibly due to a decrease in mycophenolate mofetil solubility at an increased gastric pH. The clinical relevance of reduced mycophenolic acid exposure on organ rejection has not been established in transplant patients receiving PPIs and mycophenolate mofetil. Use pantoprazole with caution in transplant patients receiving mycophenolate mofetil.

Methotrexate.

Concomitant use with methotrexate (primarily at high dose), may elevate and prolong serum levels of methotrexate and/or its metabolite, possibly leading to methotrexate toxicities.

Drugs that inhibit or induce CYP2C19 (tacrolimus, fluvoxamine).

Concomitant administration of pantoprazole and tacrolimus may increase whole blood levels of tacrolimus, especially in transplant patients who are intermediate or poor metabolisers of CYP2C19. Inhibitors of CYP2C19, such as fluvoxamine, would likely increase the systemic exposure of pantoprazole.

Coumarin anticoagulants (phenprocoumon or warfarin).

Co-administration of pantoprazole with warfarin or phenprocoumon did not affect the pharmacokinetics of warfarin, phenprocoumon or international normalised ratio (INR). However, there have been reports of increased INR and prothrombin time in patients receiving PPIs and warfarin or phenprocoumon concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding, and even death. Therefore, in patients being treated with coumarin anticoagulants (e.g. warfarin or phenprocoumon), monitoring of prothrombin time/ INR is recommended after initiation, termination or during irregular use of pantoprazole.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Pantoprazole at oral doses up to 500 mg/kg/day in male rats and 450 mg/kg/day in female rats (estimated exposure at least 60-fold the clinical exposure from the 40 mg tablet) was found to have no effect on fertility and reproductive performance.
(Category B3)
Teratological studies in rats and rabbits gave no evidence of a teratogenic potential for pantoprazole. In oral studies in rats, dose dependent toxic effects were observed on fetuses and pups: increased prenatal and postnatal deaths 450 mg/kg/day (AUC exposure approximately 60-times the clinical exposure of the 40 mg oral dose), reduced fetal weight (greater than or equal to 150 mg/kg/day) and delayed skeletal ossification and reduced pup growth (greater than or equal to 15 mg/kg/day). For the latter, a no effect dose was not established. Doses of 450 mg/kg/day were maternotoxic and may have been associated with dystocia and incomplete parturition. Penetration of the placenta was investigated in the rat and was found to increase with advanced gestation. As a result, concentrations of pantoprazole in the fetus are increased shortly before birth regardless of the route of administration.
The significance of these findings in humans is unclear. As there is no information on the safety of the drug during pregnancy in women, pantoprazole should not be used during pregnancy unless the benefit clearly outweighs the potential risk to the fetus.
Oral administration of pantoprazole to rats from late gestation to weaning at doses of 10 mg/kg/day (AUC exposure approximately the clinical exposure of the 40 mg oral dose) or greater decreased pup growth. A transient effect on one of a series of development tests (startle response) was only evident in the 30 mg/kg/day group at an age when male and female offspring showed lower body weights, paralleled with lower brain weight, than the controls. The significance of these findings for humans is unknown, and there is currently no information on the safety of pantoprazole during breastfeeding in humans. Therefore, pantoprazole should only be used during lactation if the benefits clearly outweigh the risks.

4.7 Effects on Ability to Drive and Use Machines

Pantoprazole does not exert its pharmacological action centrally, therefore it is not expected to adversely affect the ability to drive or use machines, however, adverse drug reactions such as dizziness and visual disturbances may occur (see Section 4.8 Adverse Effects (Undesirable Effects)). If affected, patients should not drive or operate machines.

4.8 Adverse Effects (Undesirable Effects)

Pantoprazole tablets are well tolerated. Most of the adverse reactions seen with treatment are of mild or moderate intensity. The following adverse reactions have been reported in patients receiving pantoprazole alone or in combination with antibiotics for H. pylori eradication in clinical trials and post-marketing surveillance.
Adverse reactions within each body system are listed in descending order of frequency (Very common: ≥ 10%; common: ≥ 1% and < 10%; uncommon: ≥ 0.1% and < 1%; rare ≥ 0.01% and < 0.1%; very rare: < 0.01%; not known: cannot be estimated from the available data). These include the following:

General disorders and administration site conditions.

Uncommon: fatigue and malaise, asthenia and increased sweating. Rare: fever, peripheral oedema and increased body temperature. Very rare: flushing, substernal chest pain and hot flushes.

Cardiovascular disorders, general.

Rare: hypertension. Very rare: circulatory collapse.

Nervous system disorders.

Uncommon: headache, dizziness. Rare: taste disorders, metallic taste. Very rare: reduced movement and speech disorder, changes to the senses of smell and taste.

Gastrointestinal system disorders.

Uncommon: diarrhoea, nausea/vomiting, abdominal distension and bloating, constipation, dry mouth, abdominal pain and discomfort. Rare: rectal disorder and colonic polyp. Very rare: faecal discolouration and increased saliva. Not known: severe eructation.
Frequency not known: withdrawal of long-term PPI therapy can lead to aggravation of acid-related symptoms and may result in rebound acid hypersecretion.

Hearing and vestibular disorders.

Very rare reports of tinnitus.

Immune system disorders.

Rare: hypersensitivity (including anaphylactic reactions including anaphylactic shock).

Hepatobiliary disorders.

Uncommon: increased liver enzymes. Rare: bilirubin increased. Very rare: hepatocellular failure, cholestatic hepatitis, jaundice. Not known: hepatocellular injury.
The occurrence of severe hepatocellular damage leading to jaundice or hepatic failure having a temporal relationship to the intake of pantoprazole has been reported with a frequency of approximately one in a million patients.

Metabolic and nutritional disorders.

Rare: hyperlipidaemias and lipid increases (triglycerides, cholesterol), weight changes. Not known: hyponatraemia, hypomagnesaemia, hypocalcaemia, hypokalaemia (hypocalcaemia and/or hypokalaemia may be related to the occurrence of hypomagnesaemia (see Section 4.4 Special Warnings and Precautions for Use).

Musculoskeletal and connective tissue disorders.

Rare: myalgia and arthralgia. Very rare: pain including skeletal pain. Not known: fracture of wrist, hip and spine.

Renal and urinary disorders.

Very rare: interstitial nephritis.

Platelet, bleeding, clotting disorders.

Very rare: increased coagulation time.

Psychiatric disorders.

Uncommon: sleep disorders. Rare: depression, hallucination, disorientation and confusion, especially in predisposed patients, as well as aggravation of these symptoms in the case of pre-existence.
Very rare reports of anxiety.

Blood and lymphatic system disorders.

Rare: anaemia, agranulocytosis. Very rare: leukopaenia, thrombocytopaenia, pancytopaenia.

Resistance mechanism disorders.

Rare: sepsis.

Respiratory system disorders.

Very rare: dyspnoea.

Reproductive system and breast disorders.

Rare: gynaecomastia.

Skin and subcutaneous tissue disorders.

Uncommon: pruritus and skin rash/ exanthema/ eruption. Rare: angioedema, urticaria. Very rare: flushing, severe skin reactions such as Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme, Lyell syndrome and photosensitivity.
Not known: subacute cutaneous lupus erythematosus, drug reaction with eosinophilia and systemic symptoms (DRESS).

Eye disorders.

Uncommon: disturbances in vision (blurred vision). Very rare: conjunctivitis.
See Tables 1 and 2.
The following safety data for patients aged 2 to 16 years (n = 250) is collated from 5 clinical studies (3001A1-109-US, 3001K1-110-US, 3001A1-322-US, 3001A1-326-US and BYK1023/MEX008). See Table 3.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at https://www.tga.gov.au/reporting-problems.

4.9 Overdose

Symptoms.

There are no known symptoms of overdosage in humans. In individual cases, 240 mg was administered i.v. or p.o. and was well tolerated. Standard detoxification procedures apply.
As pantoprazole is extensively protein bound, it is not readily dialyzable. As in any case of overdosage, treatment should be symptomatic and supportive measures should be utilised.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Pantoprazole is a proton pump inhibitor. It inhibits specifically and dose-proportionately H+/K+-ATPase, the enzyme which is responsible for gastric acid secretion in the parietal cells of the stomach.
The substance is a substituted benzimidazole which accumulates in the acidic environment of the parietal cells after absorption. There, it is converted into the active form, a cyclic sulfenamide which binds to the H+/K+-ATPase, thus inhibiting the proton pump and causing potent and long lasting suppression of basal and stimulated gastric acid secretion. As pantoprazole acts distal to the receptor level it can influence gastric acid secretion irrespective of the nature of the stimulus (acetylcholine, histamine, gastrin).
Pantoprazole's selectivity is due to the fact that it only exerts its full effect in a strongly acidic environment (pH < 3), remaining mostly inactive at higher pH values. As a result, its complete pharmacological, and thus therapeutic, effect can only be achieved in the acid secretory parietal cells. By means of a feedback mechanism this effect is diminished at the same rate as acid secretion is inhibited.
As with other proton pump inhibitors and H2-receptor inhibitors, treatment with pantoprazole causes a reduced acidity in the stomach and thereby an increase in gastrin in proportion to the reduction in acidity. The increase in gastrin is reversible.

Clinical trials.

Treatment of symptomatic reflux (GORD).

The relief of symptoms of reflux in patients who showed no oesophageal lesions on endoscopy has been shown in the following double blind, multi-centre, placebo-controlled study (245/98) using pantoprazole 20 mg once daily. Overall, 219 patients were enrolled in the study. Each patient was to have a normal oesophagus as assessed by endoscopy and to have suffered from at least one episode of heartburn of at least moderate intensity on all three days prior to inclusion into the study. Additionally, patients were to have a history of reflux symptoms (heartburn, acid eructation, pain on swallowing) for at least three months prior to entry into the study. Efficacy of pantoprazole 20 mg is shown in Table 4.

Acute treatment of mild reflux oesophagitis.

In two randomised, double blind, multicentre studies (BGSA006 and FK3034) 410 patients with mild gastroesophageal reflux disease (GORO) (Savary-Miller stage 1) were treated with either pantoprazole 20 mg once daily before breakfast or ranitidine 300 mg once daily at bedtime. Superiority of pantoprazole 20 mg in terms of healing rates compared to ranitidine after four and eight weeks is shown in Table 5. The difference in healing rates was statistically significant at all time points in the intention to treat and per protocol patient groups.

Maintenance of healed reflux oesophagitis in patients previously treated for moderate to severe reflux oesophagitis.

Three randomised, double blind, parallel group trials examined the efficacy of pantoprazole in the maintenance of healed reflux oesophagitis in patients aged 18 to 88 years treated for moderate to severe reflux oesophagitis over 12 months. The primary endpoint was time to endoscopically confirmed relapse; however, the median was not reached in the pantoprazole groups at the end of 12 months. The results for the incidence of relapse in patients with data from at least one follow-up visit are outlined in Table 6.
Pantoprazole 20 mg and 40 mg/day doses were therapeutically equivalent based on the pre-defined equivalence criterion of the 90% confidence interval of the difference between doses being within ± 20%.
Four uncontrolled trials with varying periods of follow-up support the long-term efficacy of pantoprazole 40-80 mg/day in the maintenance of healed reflux oesophagitis in patients previously treated for moderate to severe reflux oesophagitis. Two of the trials included patients with gastric and duodenal ulcer. The incidence of relapse at 1 year was 12-15%, 2 years 22-25% and 6 years 40%.
Safety data is available from the 1584 patients involved in the 7 long-term clinical studies. 904 patients have been treated with pantoprazole for at least 1 year, and 273, 112, 68, 47 and 17 have been treated for at least 2, 3, 4, 5 and 6 years, respectively. In total, 108 (6.8%) patients experienced serious adverse events (EC definition), of which all but 6 were classified as being causally unrelated to pantoprazole (4 cases with 40 mg pantoprazole: colonic polyp; abdominal pain and rectal disorder; diarrhoea and abdominal pain, sepsis versus 2 cases with high-dose pantoprazole: anaemia and hypertension) (see Section 4.8 Adverse Effects (Undesirable Effects)). Additionally, in the open on-going studies, patients were assessed by biopsy and no evidence of dysplastic or neoplastic endocrine growth was found.

Prevention of gastroduodenal lesions and dyspeptic symptoms associated with nonselective NSAIDs in increased risk patients with a need for continuous non-selective NSAID treatment.

Two randomised, double blind, multi-centre studies (205/2000 and 129/2000) examined the efficacy and safety of pantoprazole in the prevention of NSAID associated gastroduodenal ulcers, petechiae, erosions and dyspeptic symptoms in patients with arthritis on continuous treatment with NSAIDs and an increased risk of developing gastrointestinal lesions.
The primary endpoint for both studies was the 'therapeutic failure' rate after six months, defined as 'endoscopic failure' (i.e. more than ten erosions or petechiae, peptic ulcer, reflux oesophagitis) or premature study termination due to at least likely related adverse event or due to severe gastrointestinal symptoms.

Study 205/2000.

A total of 515 patients were included into the study. Patients were randomised to receive either pantoprazole 20 mg daily (n = 257) or misoprostol 200 microgram twice daily (n = 258). Efficacy of pantoprazole 20 mg is shown in Table 7.
Pantoprazole 20 mg once daily was statistically significantly superior to misoprostol 200 microgram twice daily with regard to 'therapeutic failure' and to 'endoscopic failure'. Reflux oesophagitis was included as an efficacy endpoint in the study which may have biased the results in favour of pantoprazole. A causal association between NSAIDs and reflux oesophagitis has not been established. In addition, proton pump inhibitors such as pantoprazole have documented beneficial treatment effects on reflux oesophagitis while misoprostol (a prostaglandin E1 analogue) has negligible therapeutic effects.

Study 129/2000.

A total of 595 patients were included into the study. Patients were randomised to receive either pantoprazole 20 mg daily (n = 196), pantoprazole 40 mg daily (n = 199) or omeprazole 20 mg daily (n = 200). Efficacy results are shown in Table 8.
All three treatments, pantoprazole 20 mg, pantoprazole 40 mg and omeprazole 20 mg, were proven to be of equivalent and high efficacy.

5.2 Pharmacokinetic Properties

Absorption.

Pantoprazole is rapidly absorbed and the maximal plasma concentration appears after one single oral dose. After single and multiple oral doses, the median time to reach maximum serum concentrations was approximately 2.5 h. In the fasted state, it was found that the Cmax of Sozol 40 mg tablets was 3.6 microgram/mL. Terminal half-life is approximately 1 h.
Pharmacokinetics do not vary after single or repeated administration. The plasma kinetics of pantoprazole are linear (in the dose range of 10 to 80 mg) after both oral and intravenous (IV) administration.
Pantoprazole is completely absorbed after oral administration. The absolute bioavailability of the tablet is approximately 77%. Concomitant intake of food had no influence on AUC, maximum serum concentrations and thus bioavailability.

Distribution.

The serum protein binding of pantoprazole is approximately 98%. Volume of distribution is approximately 0.15 L/kg and clearance is approximately 0.1 L/h/kg.

Metabolism.

Pantoprazole is extensively metabolized in the liver through the cytochrome P450 (CYP) system. Pantoprazole metabolism is independent of the route of administration (intravenous or oral). The main metabolic pathway is demethylation, by CYP2C19, with subsequent sulfation; other metabolic pathways include oxidation by CYP3A4.
There is no evidence that any of the pantoprazole metabolites have significant pharmacologic activity. CYP2C19 displays a known genetic polymorphism due to its deficiency in some sub-populations (e.g. 3% of Caucasians and African-Americans and 17-23% of Asians). Although these sub-populations of slow pantoprazole metabolizers have elimination half-life values of 3.5 to 10.0 hours, they still have minimal accumulation (≤ 23%) with once daily dosing.

Excretion.

Pantoprazole is rapidly eliminated from serum and is almost exclusively metabolised in the liver. Renal elimination represents the most important route of excretion (approximately 80%) for the metabolites of pantoprazole, the rest are excreted with the faeces. The main metabolite in both the serum and urine is desmethyl-pantoprazole which is conjugated with the sulphate. The half-life of the main metabolites (approximately 1.5 h) is not much longer than that of pantoprazole.

Special populations.

In patients with liver cirrhosis given a single 40 mg tablet, the half-life increases to between 7 and 9 h and the AUC values are increased by a factor of 6-8 but the maximum serum concentration increases only slightly by a factor of 1.5 in comparison with healthy subjects. After a single 20 mg tablet, AUC increased 3-fold in patients with mild hepatic impairment and 5-fold in patients with severe hepatic impairment compared with healthy controls. Mean elimination half-life was 3.3 h in mild hepatic impairment and 6.0 h in severe hepatic impairment compared with 1.1 h in controls. The maximum serum concentration only increased slightly by a factor of 1.3 compared with healthy subjects.
In patients with renal impairment (including those undergoing dialysis) no dose reduction is required. Although the main metabolite is moderately increased, there is no accumulation. The half-life of pantoprazole is as short as in healthy subjects. Pantoprazole is poorly dialyzable.
The slight increase in AUC and Cmax in elderly volunteers compared with their younger counterparts is also not clinically relevant.

5.3 Preclinical Safety Data

Genotoxicity.

A number of in vitro and in vivo genotoxicity assays covering mutagenicity, clastogenicity and DNA damage endpoints were conducted on pantoprazole and the results were generally negative. Exposures achieved in the in vivo tests in mice and rats were well in excess of exposures expected clinically. However, pantoprazole was clearly positive in carefully conducted cytogenetic assays in human lymphocytes in vitro, both in the presence and absence of metabolic activation. Omeprazole was also positive in a comparable test conducted in the same laboratory, suggesting a possible class effect. A minute amount of radioactivity was bound to rat hepatic DNA after treatment with 200 mg/kg/day pantoprazole for 14 days. This is an estimated exposure 24-fold the clinical exposure from the 40 mg tablet. No distinct DNA-adduct has been detected.
Pantoprazole was found to be negative in the following studies: in vivo chromosome aberration assay in rat and bone marrow (126E/95), mouse lymphoma test (222E/95) and a gene mutation test in Chinese hamster ovary cells (in vitro) (188E/95). In addition, toxicokinetic studies were conducted in rats at the doses used in the bone marrow assay (50 to 1200 mg/kg) (56E/96) and in mice at the high dose from the earlier micronucleus test (710 mg/kg) (89E/96). Pantoprazole exposure was high with the respective rat and mouse plasma AUCs being 7 to 100 and 9- to 12-fold the clinical exposure from a 40 mg tablet.

Carcinogenicity.

A two year oral carcinogenicity study in Sprague Dawley rats at doses up to 200 mg/kg/day gastric carcinoids were found after pantoprazole treatment at doses greater than 0.5 mg/kg/day in females and greater than 5 mg/kg/day in males, with none observed in controls. The estimated exposure (based on AUC) from these doses are at, or below, clinical exposure from a 40 mg tablet. The development of gastric tumours is attributed to chronic elevation of serum gastrin levels with associated histopathological changes in the gastrointestinal system.
In both male and female rats, the development of hepatocellular adenomas was increased at doses greater than 5 mg/kg/day and the development of hepatocellular carcinomas was increased at doses greater than 50 mg/kg/day, with respective estimated exposures of 1- and 9-fold the AUC of the 40 mg clinical dose. Hepatocellular tumours, which were also observed in female mice at oral doses greater than 25 mg/kg/day (exposure similar to clinical exposure), may be associated with pantoprazole-induced increases in hepatic enzyme activity.
Treatment with pantoprazole at doses greater than 50 mg/kg/day (exposure approximately 9-fold clinical exposure) also increased the development of thyroid follicular cell adenomas in male and female rats. Several studies in rats were conducted to investigate the effect of pantoprazole on the thyroid, the results of which suggested that the effect may be secondary to the induction of enzymes in the liver.
In a more recent carcinogenicity study, Fischer rats were studied using lower doses (5, 15 and 50 mg/kg, 0.5-, 2- and 7-fold the clinical AUC, respectively). Gastric carcinoids were detected at all doses in females and at the 15 and 50 mg/kg doses in males, while none were detected in controls. No metastases of these carcinoids were detected. There was no increase in incidence of liver tumours. The dose of 15 mg/kg is seen to be the no-effect level for liver tumours in rodents.
Consideration of the possible mechanisms involved in the development of the above drug-related tumour types suggests that it is unlikely that there is any carcinogenic risk in humans at therapeutic dose levels of pantoprazole for short term treatment.

6 Pharmaceutical Particulars

6.1 List of Excipients

Pantoprazole contains the following excipients: mannitol, sodium carbonate, sodium starch glycollate, crospovidone, colloidal anhydrous silica, calcium stearate, hypromellose, macrogol 6000, sodium hydroxide, Eudragit L30-D55 (ARTG No. 3700) and Opadry AMB aqueous moisture barrier coating system 80W52172 Yellow (ARTG No. 106688).
Sozol tablets are gluten free.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf-life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 25°C.

6.5 Nature and Contents of Container

The blister is made of Al/Al.
Sozol 20 mg are available in blister packs of 30 tablets.
Sozol 40 mg are available in blister packs of 30 tablets.
Other pack sizes currently not marketed are 5, 14, 15, 28, 50, 56, 60, 100 and 140 tablets.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Pantoprazole is a substituted benzimidazole which inhibits basal and stimulated gastric secretion. It is a white to off white crystalline powder. Freely soluble in water and in ethanol (96 per cent), practically insoluble in hexane. Solubility is low at neutral pH and increases with increasing pH.
Chemical name: sodium 5-(difluoromethoxy)-2- [(RS)-[(3,4-dimethoxy pyridin-2-yl)methyl]sulphinyl] benzimidazol-1-ide sesquihydrate.
Molecular formula: C16H14F2N3NaO4S 1½ H2O.
Molecular weight: 432.4 (sodium salt x 1.5 H2O).

Chemical structure.


CAS number.

Cas No.: 164579-32-2.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription only medicine.

Summary Table of Changes