QRD update.

4.5 Interaction with other medicinal products and other forms of interaction

[...]

Erlotinib and medicinal products altering pH

Concomitant administration of 300 mg ranitidine and erlotinib decreased erlotinib exposure [AUC] and maximum concentrations [Cmax] by 33% and 54%, respectively. However, when erlotinib was dosed in a staggered manner 2 hours before or 10 hours after ranitidine 150 mg b.i.d., erlotinib exposure [AUC] and maximum concentrations [Cmax] decreased only by 15% and 17%, respectively.

 

Updated address of the MAH

4.4 Special warnings and precautions for use

 

Treatment with a histamine H2-antagonist may mask symptoms associated with carcinoma of the stomach and may therefore delay diagnosis of the condition.

 

Ranitidine is excreted via the kidney and so plasma levels of the drug are increased in patients with renal impairment (creatine clearance less than 50ml/min). Ranitidine products are not suitable for these patients without medical supervision.

 

Rare clinical reports suggest that ranitidine may precipitate acute porphyric attacks. Ranitidine should therefore be avoided in patients with a history of acute porphyria.

The following patients are advised to seek their doctor’s advice before taking ranitidine products:

 

Patients with renal impairment (creatine clearance less than 50ml/min) and/or hepatic impairment. Patients under regular medical supervision.

Patients taking medications either physician prescribed or self-prescribed.

Patients of middle age or older with new or recently changed dyspeptic symptoms. Patients with unintended weight loss in association with dyspeptic symptoms.

Patients taking non-steroidal anti-inflammatory drugs, especially in those with a history of ulcer should consult their doctor prior to use.

 

In patients such as the elderly, persons with chronic lung disease, diabetes or the immunocompromised, there may be an increased risk of developing community acquired pneumonia. A large epidemiological study showed an increased risk of developing community acquired pneumonia in current users of ranitidine alone versus those who had stopped treatment, with an observed adjusted relative risk increase of 1,82 (95% CI, 1,26 - 2,64).

4.6 Fertility, pregnancy and lactation

 

Fertility

 

There are no data on the effects of ranitidine on human fertility. In animal studies, no effect on fertility was observed.

 

Pregnancy

 

Ranitidine crosses the placenta. As with other drugs, ranitidine products should not be taken in pregnancy without consulting a doctor.

 

Lactation

 

Ranitidine is excreted in human breast milk. Women who are breastfeeding are advised to speak to their doctor before taking ranitidine products.

4.8 Undesirable effects

 

The following convention has been utilised for the classification of undesirable effects:

Very common (2:1/10), common (2:1/100, <1/10), uncommon (2:1/1000, <1/100), rare (2:1/10,000, <1/1000), very rare ( <1/10,000). Adverse event frequencies have been estimated from spontaneous reports from post-marketing data.

Blood & Lymphatic System Disorders

Very rare: Blood count changes (leucopenia, thrombocytopenia). These are usually reversible. Agranulocytosis or pancytopenia, sometimes with marrow hypoplasia or marrow aplasia.

 

Immune System Disorders

Rare: Hypersensitivity reactions (urticaria, angioneurotic oedema, fever, bronchospasm, hypotension and chest pain). Very rare: Anaphylactic shock.

These events have been reported after a single dose.

 

Psychiatric Disorders

Very rare: Reversible mental confusion, depression and hallucinations. These have been reported predominantly in severely ill and elderly patients.

 

Nervous System Disorders

Very rare: Headache (sometimes severe), dizziness and reversible involuntary movement disorders.

 

Eye disorders

Very rare: Reversible blurred vision.

There have been reports of blurred vision, which is suggestive of a change in accommodation.

 

Cardiac Disorders

Very rare: As with other H2 receptor antagonists bradycardia and A-V Block.

 

Vascular Disorders

Very Rare: Vasculitis

 

Gastrointestinal Disorders

Very Rare: Acute pancreatitis. Diarrhoea.

Uncommon: Abdominal pain, constipation, nausea (these symptoms mostly improved during continued treatment).

 

Hepatobiliary Disorders

Rare: Transient and reversible changes in liver function tests.

Very Rare: Hepatitis (hepatocellular, hepatocanalicular or mixed) with or without jaundice, these were usually reversible.

 

Skin and Subcutaneous Tissue Disorders

Rare: Skin Rash

Very Rare: Erythema multiforme, alopecia.

 

Musculoskeletal and Connective Tissue Disorders

Very Rare: Musculoskeletal symptoms such as arthralgia and myalgia.

 

Renal and Urinary Disorders

Very Rare: Acute interstitial nephritis

Rare: Elevation of plasma creatinine (usually slight; normalised during continued treatment)

 

Reproductive System and Breast Disorders

Very Rare: Reversible impotence and breast conditions (such as gynaecomastia and galactorrhoea)

 

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. Website: www.hpra.ie; e-mail: medsafety@hpra.ie

5.2 Pharmacokinetic properties

 

The bioavailability of ranitidine is consistently about 50%. Peak concentrations in plasma, normally in the range 236- 270 ng/ml, after a 75 mg dose, occur 2-3 hours after oral administration. Concentrations of ranitidine in plasma are proportional to doses up to and including 300 mg.

 

Ranitidine is not extensively metabolised.  Elimination of the drug is primarily by tubular excretion.  The elimination half-life is 2-3 hours.

 

In balance studies with 150 mg 3H-ranitidine 93% of an intravenous dose was excreted in urine and 5% in faeces; 60- 70% of an oral dose was excreted in the urine and 26% in the faeces. Analysis of urine excreted in the first 24 hours after dosing showed that 70% of the intravenous dose and 35% of the oral dose were eliminated unchanged. The metabolism of ranitidine is similar after both oral and intravenous dosing; about 6% of the dose being excreted in urine as the N-oxide, 2% as the S-oxide, 2% as desmethylranitidine and 1-2% as the furoic acid analogue.

 

Special patient populations: In patients over 50 years of age, half-life is prolonged (3-4 h) and clearance is reduced, consistent with the age-related decline of renal function. However, systematic exposure and accumulation are 50% higher. This difference exceeds the effect of declining renal function, and indicates increased bioavailability in older patients.

6.3  Shelf life

 

3 years.

 

6.4  Special precautions for storage

 

Store below 25°C.

Tablets should not be removed from blisters until immediately prior to use.

$04.6  Fertility, pregnancy andlactation$0$0PREVIOUS VERSION: N/A$0$0UPDATED VERSION: $0$0Fertility $0$0$0$0There are no data on the effects of ranitidine onhuman fertility. There were no effects on male and female fertility in animalstudies.$0$05.1Pharmacodynamic properties$0$0PREVIOUS VERSION: Ranitidine is a specific rapidly acting histamine H2-receptor antagonist. It inhibits basal and stimulated secretion of gastric acid, reducingboth the volume and the acid and pepsin content of the secretion. Ranitidine has a long durationof action and a single 75mg dose effectively suppresses gastric acid secretionfor at least 12 hours. Clinicalstudies have shownthat Zantac 75 can relievethe symptoms during a maximumof twelve hours.$0$0$0$0$0UPDATED VERSION:$0$0ATC Code: A02BA02$0$0Pharmacotherapeutic group: H₂-receptorantagonists. $0$0Ranitidineis a specific, rapidly acting histamine H₂-antagonist.  It inhibits basal and stimulated secretion ofgastric acid, reducing both the volume and the acid and pepsin content of thesecretion.Rantidinehas a long duration of action and a single 75 mg dose effectively suppressesgastric acid secretion for at least 12 hours.Clinical studies have shown that Zantac 75 can relieve symptoms during amaximum of twelve hours.$0$05.3  Preclinical safety data$0$0PREVIOUS VERSION: No Particulars.$0$0UPDATED VERSION: Non-clinicaldata revealed no special hazard for humans based on conventional studies ofsafety pharmacology, repeated-dose toxicity, genotoxicity, carcinogenic potentialand toxicity to reproduction and development.$0$0$010       DATE OF REVISIONOF THE TEXT$0$0$0PREVIOUS VERSION: September 2013$0$0UPDATED VERSION: 5^th September 2014$0

$0·Sections 4.2, 4.4 and 4.8 of the SPC are updatedin line with the GSK Global data safety sheet.$0$0

Section 7 MAH Holder address changed from GSK Ireland to:

Chefaro Ireland Limited First Floor

Block A

The Crescent Building Northwood Office Park

Dublin 9

Ireland

Section 8 Marketing Authoriation Number to:

PA 1186/013/001

Section 10 Revision date to January 2013

Section 10 - date of revision is corrected

Section 4.4

Formating updates

Section 4.5

Treatment with a histamine H₂-antagonist may mask symptoms associated with carcinoma of the stomach and may therefore delay diagnosis of the condition. Patients of middle age or older with new or recently changed dyspeptic symptoms, or with unintended weight loss in association with dyspeptic symptoms should consult a doctor before use.

 

Rare clinical reports suggest that ranitidine may precipitate acute porphyric attacks.  Ranitidine should therefore be avoided in not be given to patients with a history of acute porphyria.

 

Patients with severe renal/hepatic impairment, those under regular medical supervision, and those who are taking any medications (either physician or self prescribed) are advised to consult their doctor prior to use. Ranitidine is excreted through via the kidney and so plasma levels of the drug are increased in patients with severe renal impairment.  Zantac 75 are not suitable for these patients.

 

 

The following patients are advised to seek their doctor’s advice before taking Zantac 75:

 

·         Patients with severe renal and/or hepatic impairment.

·         Patients under regular medical control.

·         Patients taking medication prescribed by a physician or self-prescribed.

·         Patients of middle age or older with new or recently changed dyspeptic symptoms.

·         Patients with unintended weight loss in association with dyspeptic symptoms.

·         Patients with a risk of developing ulcers or a history of peptic ulcer (e.g. patients taking NSAIDs).

 

In patients such as the elderly, persons with chronic lung disease, diabetes or the immunocompromised, there may be an increased risk of developing community acquired pneumonia. A large epidemiological study showed an increased risk of developing community acquired pneumonia in current users of ranitidine alone H2 receptor antagonists versus those who had stopped treatment, with an observed adjusted relative risk increase of 1.63 (95% CI, 1.07–2.48) 1,82 (95% CI, 1,26–2,64).

 

Patients taking non-steroidal anti-inflammatory drugs, especially in those with a history of ulcer should consult their doctor prior to use.

 

4.5.      Interaction with other medicaments and other forms of interaction

 

Ranitidine has the potential to affect the absorption, metabolism or renal excretion of other drugs.  The altered pharmacokinetics may necessitate dosage adjustment of the affected drug or discontinuation of treatment.

 

Interactions occur by several mechanisms including:

 

1) Inhibition of cytochrome P450-linked mixed function oxygenase system:

Ranitidine does not inhibit the hepatic cytochrome P450-linked mixed function oxygenase system at therapeutic doses.  Accordingly, ranitidine Ranitidine in standard at usual therapeutic doses does not potentiate the actions of drugs which are inactivated by this enzyme; these include system such as diazepam, lidocaine, phenytoin, propranolol and theophylline. and warfarin.  There have been reports of altered prothrombin time with coumarin anticoagulants (e.g. warfarin). Due to the narrow therapeutic index, close monitoring of increased or decreased prothrombin time is recommended during concurrent treatment with ranitidine.

 

2) Alteration of gastric pH:

The bioavailability of certain drugs may be affected.  This can result in either an increase in absorption (e.g. triazolam, midazolam, glipizide) or a decrease in absorption (e.g. ketoconazole, atazanavir, delaviridine, gefitnib).

 

If high doses (2 g) of sucralfate are co-administered with ranitidine the absorption of the latter may be reduced. This effect is not seen if sucralfate is taken after an interval of 2 hours.

 

4.6.      Pregnancy and lactation

 

Insufficient data is available to assess the possible risks of the use of ranitidine in pregnant or lactating women.  Ranitidine crosses the placenta and is also excreted in breast milk; however, the clinical relevance is not clear.  Zantac 75 should therefore not be taken during pregnancy and lactation without consulting a doctor.

 

Pregnancy

Ranitidine crosses the placenta. As with other drugs, ranitidine products should not be taken in pregnancy without consulting a doctor.

 

Lactation

Ranitidine is excreted in human breast milk.  Women who are breastfeeding are advised to speak to their doctor before taking ranitidine products.

 

4.7.      Effects on ability to drive and use machines

 

Insufficient data on the effects on ability to drive and to operate machines is available.

None reported.

 

 

4.8.      Undesirable effects

 

The following convention has been utilised for the classification of undesirable effects: very common (>1/10), common (>1/100, <1/10), uncommon (>1/1000, <1/100), rare (>1/10,000, <1/1000), very rare (1/10,000).

Adverse event frequencies have been estimated from spontaneous reports from post-marketing data.

 

Blood & Lymphatic System Disorders

Very Rare:       Blood count changes (leucopenia, thrombocytopenia). These are usually reversible. Agranulocytosis or pancytopenia, sometimes with *marrow hypoplasia or marrow aplasia.

 

Immune System Disorders

Rare:                Hypersensitivity reactions (urticaria, angioneurotic oedema, fever, bronchospasm, hypotension and chest pain).

Very Rare:       Anaphylactic shock

These events have been reported after a single dose.

 

Psychiatric Disorders

Very Rare:       Reversible mental confusion, depression and hallucinations.

These have been reported predominantly in severely ill and elderly patients.

 

Nervous System Disorders

Very Rare:       Headache (sometimes severe),dizziness and reversible involuntary movement disorders.

 

Eye Disorders

Very Rare:       Reversible blurred vision.

There have been reports of blurred vision, which is suggestive of a change in accommodation.

 

Cardiac Disorders

Very Rare:       As with other H2 receptor antagonists bradycardia and A-V Block.

 

Vascular Disorders

Very Rare:       Vasculitis.

 

Gastrointestinal Disorders

Very Rare:       Acute pancreatitis. Diarrhoea.

Uncommon:    Abdominal pain, constipation, nausea (these symptoms mostly improved                            during continued treatment).

 

Hepatobiliary Disorders

Rare:                Transient and reversible changes in liver function tests.

Very Rare        Hepatitis (hepatocellular, hepatocanalicular or mixed) with or without jaundice, these were usually reversible.

 

Skin and Subcutaneous Tissue Disorders

Rare:                Skin Rash.

Very Rare:       Erythema multiforme, alopecia.

 

Musculoskeletal and Connective Tissue Disorders

Very Rare:       Musculoskeletal symptoms such as arthralgia and myalgia.

 

Renal and Urinary Disorders

Very rare:        Acute interstitial nephritis.

Rare:                Elevation of plasma creatinine (usually slight; normalised during continued                         treatment)

 

Reproductive System and Breast Disorders

Very Rare:       Reversible impotence. *Breast symptoms in men. and breast conditions (such                      as gynaecomastia and galactorrhoea)

 

Paediatric population

The safety of ranitidine has been assessed in children aged 0 to 16 years with acid-related disease and was generally well tolerated with an adverse event profile resembling that in adults. There are limited long term safety data available, in particular regarding growth and development.

 

4.9.      Overdose

 

Symptoms and Signs

Ranitidine is very specific in action and accordingly no particular problems are expected following overdosage with the drug ranitidine formulations. Up to 6g per day has been administered without untoward effect in patients with Zollinger-Ellison syndrome.

Treatment

In case of overdosage symptomatic and supportive therapy should be given as appropriate.

is recommended.  If necessary, the drug may be removed from the plasma by haemodialysis.

Section 4.5 - correction of formatting error

Section 4.4.

The following has been added:

In patients such as the elderly, persons with chronic lung disease, diabetes or the immunocompromised, there may be an increased risk of developing community acquired pneumonia. A large epidemiological study showed an increased risk of developing community acquired pneumonia in current users of H2 receptor antagonists versus those who had stopped treatment, with an observed adjusted relative risk increase of 1.63 (95% CI, 1.07–2.48).