PIRFENEX Tablets (Pirfenidone)

Table of Content

For the use of a Pulmonologist only

 

Black Box Warning

The use of pirfenidone has been shown to cause an abnormal chromosomal structure on exposure to light in genotoxicity tests; therefore, it is important to explain to the patient about the potential of the drug to cause carcinogenesis of the skin on exposure to light. Pirfenidone should only be prescribed under the supervision of a physician familiar with the treatment of idiopathic pulmonary fibrosis (IPF).

Qualitative and Quantitative Composition

PIRFENEX-200

Each film-coated tablet contains:

Pirfenidone IP ............... 200 mg

Colour: Titanium Dioxide IP

PIRFENEX-400

Each film-coated tablet contains:

Pirfenidone IP ...............400 mg

Colour: Titanium Dioxide IP

PIRFENEX-600

Each film-coated tablet contains:

Pirfenidone IP ............... 600 mg

Colour: Titanium Dioxide IP

Dosage Form(S) And Strength(S)

Oral tablet; 200 mg, 400 mg, 600 mg

Clinical Particulars

Therapeutic Indications

Pirfenidone is indicated for the treatment of idiopathic pulmonary fibrosis (IPF).

Posology and Method of Administration

The initial dose for adults is 200 mg, three times a day (600 mg/day), after a meal. Gradually increase the dose to 800 mg, three times a day (2,400 mg/day), under observation (as per Recommendations for Dosage Adjustmentbelow). Furthermore, appropriately increase or decrease the dose from time to time depending upon the symptoms.

Recommendations for Dosage Adjustment

Start with a 200 mg dose given three times a day (600 mg/day). After 2 weeks, gradually increase the dose by 200 mg at a time. It is desirable to maintain or achieve a final dose of 800 mg at a time (2,400 mg/day).

Table 1: Suggested Dosage Titration for Pirfenex in Patients with IPF

Treatment days

 

Dose to be achieved with PIRFENEX

No. of tablets to be taken to achieve the desired dose

Days 0–14

600 mg/day

1 tablet of 200 mg every 8hours

Days 15–28

1,200 mg/day

1 tablet of 400 mg every 8hours

Days 29–42

1,800 mg/day

1 tablet of 600 mg every 8hours

Day 43 onwards

2,400 mg/day

2 tablet of 400 mg every 8hours

Patients who miss 14 consecutive days or more of pirfenidone treatment should re-initiate therapy by undergoing the initial dose titration regimen up to the recommended daily dose.

For treatment interruption of less than 14 consecutive days, the dose can be resumed at the previous recommended daily dose without titration.

Dose Adjustments and Other Considerations for Safe Use

Gastrointestinal Events:In patients who experience intolerance to therapy due to gastrointestinal side effects, it is recommended to administer pirfenidone after food to prevent/reduce side effects. If symptoms persist, pirfenidone may be reduced to a 200–400 mg dose given two to three times/day after food with re-escalation to the recommended daily dose as tolerated. If symptoms continue, patients may be instructed to interrupt treatment for 1 to 2 weeks to allow symptoms to resolve.

Photosensitivity Reaction or Rash:Patients who experience a mild-to-moderate photosensitivity reaction or rash should be reminded of the instruction to use a sunblockdaily and to avoid sun exposure (seeSpecialWarnings and Precautions for Use). The dose of pirfenidone may be reduced to 600 mg/day (200 mg three times a day). If the rash persistsafter 7 days, pirfenidone should be discontinued for 15 days, with re-escalation to the recommended daily dose in the same manner as the dose escalation period. Patients who experience severe photosensitivity reaction or rash should be instructed to interrupt the dose and to seek medical advice. Once the rash has resolved, pirfenidone may be re-introduced and re-escalated up to the recommended daily dose at the discretion of the physician (seeSpecialWarnings and Precautions for Use).

Hepatic Function:In the event of significant elevation of alanine and/or aspartate aminotransferases (ALT/AST) with or without bilirubin elevation, the dose of pirfenidoneshould be adjusted or treatment discontinued according to the guidelines listed below (seeSpecialWarnings and Precautions for Use).

Recommendations in Case of ALT/AST Elevations

• If a patient exhibits an aminotransferase elevation to >3 to ≤5 x the upper limit of normal (ULN) after starting pirfenidone therapy, confounding medicinal products should be discontinued, other causes excluded, and the patient monitored closely. If clinically appropriate the dose of pirfenidone should be reduced or interrupted. Once liver function tests are within normal limits pirfenidone may be re-escalated to the recommended daily dose if tolerated.

• If a patient exhibits an aminotransferase elevation to ≤5 x ULN accompanied by symptoms or hyperbilirubinaemia, pirfenidone should be discontinued and the patient should not be rechallenged.

• If a patient exhibits an aminotransferase elevation to >5 x ULN, pirfenidone should be discontinued and the patient should not be rechallenged.

Use in Special Populations

Patients with Hepatic Impairment

No dose adjustment is necessary in patients with mild-to-moderate hepatic impairment (i.e. Child-Pugh Class A and B). However, since plasma levels of pirfenidone may be increased in some individuals with mild-to-moderate hepatic impairment, caution should be used with pirfenidone treatment in this population. Patients should be monitored closely for signs of toxicity especially if they are concomitantly taking a known CYP1A2 inhibitor (seeSpecialWarnings and Precautions for Use). Pirfenidone has not been studied in patients with severe hepatic impairment or end stage liver disease, and it should not beused in patients with these conditions (see Special Warnings and Precautions for Use). It is recommended to monitor liver function during treatment, and dose adjustments may benecessary in the event of elevations (seeSpecial Warnings and Precautions for Use)and Recommendations for Dose Adjustment).

Patients with Renal Impairment

No dose adjustment is necessary in patients with mild-to-moderate renal impairment. Pirfenidone therapy should not be used in patients with severe renal impairment the adverse reactions are presented in order of decreasing seriousness.

Table 2: Adverse Reactions by SOC and MedDRA Frequency

Infections and infestations

Common

Upper respiratory tract infection; urinary tract infection

Metabolism and nutrition disorders

Common

 Weight decreased; anorexia; decreased appetite

Psychiatric disorders

Common

Insomnia

Nervous system disorders

Common

Dizziness; headache; somnolence; dyspepsia

Vascular disorders

Common

Hot flush

Respiratory, thoracic and mediastinal disorders

Common:

Dyspnoea; cough; productive cough

Gastrointestinal disorders

Very common

Common

 

Dyspepsia; nausea; diarrhoea

Gastro-oesophageal reflux disease; vomiting; abdominal distension; abdominal discomfort; abdominal pain; abdominal pain upper; stomach discomfort;gastritis; constipation; flatulence

Hepatobiliary disorders

Common

ALT increased; AST increased; gamma glutamyl transferase increased

Skin and subcutaneous tissue disorders

Very common

Common

Photosensitivity reaction; rash

Pruritus; erythema; dry skin; rash erythematous; rash macular; rash pruritic

Musculoskeletal and connective tissue disorders

 

Common

Myalgia; arthralgia

General disorders and administration site conditions

 

Very common

Common

Fatigue

Asthenia; non-cardiac chest pain

Injury poisoning and procedural complications

 

Common

Sunburn

1 Identified through postmarketing surveillance

Reporting of Side Effects

If you experience any side effects, talk to your doctor or pharmacist or write to drugsafety@cipla.com. You can also report side effects directly via the National Pharmacovigilance Programme of India by calling on 1800 180 3024or you can report to Cipla Ltd. on 1800 267 7779. By reporting side effects, you can help provide more information on the safety of this product.

Overdose

Inadequate information available. Multiple doses of pirfenidone up to a dose of 4,806 mg/day were administered as six 267 mg capsules three times daily to healthy adult volunteers over a 12-day dose escalation period. Adverse reactions were mild, transient, and consistent with the most frequently reported adverse reactions for pirfenidone.

In the event of a suspected overdose, supportive medical care should be provided including monitoring of vital signs and close observation of the clinical status of the patient.

Pharmacological Properties

Mechanism of Action

Pirfenidone is a pyridine molecule with anti-inflammatory and antifibrotic activities that have been reported both in vitro and in vivo. The mechanism of action of pirfenidone has not been fully established. However, existing data suggest that pirfenidone exerts both antifibrotic and anti-inflammatory properties in a variety of in vitro systems and animal models of pulmonary fibrosis (bleomycin- and transplant-induced fibrosis).

Pharmacodynamicsproperties

IPF is a chronic fibrotic and inflammatory pulmonary disease affected by the synthesis and release of pro-inflammatory cytokines, including tumour necrosis factor-alpha (TNF-α) and interleukin-1-beta (IL-1β), and pirfenidone has been shown to reduce the accumulation of inflammatory cells in response to various stimuli.

Pirfenidone attenuates fibroblast proliferation, production of fibrosis-associated proteins and cytokines, and the increased biosynthesis and accumulation of extracellular matrix in response to cytokine growth factors such as, transforming growth factor-beta (TGF-β) and platelet-derived growth factor (PDGF).

Ex vivo, pirfenidone inhibited fibroblast proliferation, differentiation and related collagensynthesis and inhibited its degradation. Pirfenidone reduced the production of other mediators of fibrogenesis, such as fibronectin and connective tissue growth factor . Moreover, in a murine macrophage-like cell line , pirfenidone inhibited TNF-αsynthesis in vitro, whereas it increased the production of IL-10 (with anti-inflammatory activity) in the murine endotoxin shock model in vivo. Pirfenidone has also been shown to reduce the levels of platelet-derived growth factors, A and B in bronchoalveolar lavage in a hamster model of bleomycin-induced lung fibrosis.

Pharmacokinetics properties

Plasma Concentrations

Plasma concentrations and pharmacokinetic parameters of pirfenidone in 6 healthy adult men, given 200 mg, 400 mg and 600 mg as a fasting, single oral administration, are shown in Figure 1 and Table 3.

 

Figure 1: Plasma concentrations on Fasting after a Single Dose
Table 3:  Pharmacokinetic Parameters (n = 6)

Dose quantity (mg)

Cmax

(µg/mL)

Tmax (hr)

AUC0-48

(µg.hr/mL)

T1/2(hr)

200

3.88 +0.82

0.75 + 0.27

13.97 +2.71

2.10 + 0.45

400

9.24 +1.74

0.58 + 0.20

29.10  + 11.77

1.96 + 0.55

600

10.57 + 1.78

0.83 + 0.26

37.03 + 11.97

1.76 + 0.40

  (Measurement method: HPLC) (Mean + SD)

Similarly, the plasma concentrations achieved after repeated doses of 200 mg, 400 mg and 600 mg, respectively, and by gradually increasing the dosages to three times a day at morning, afternoon and evening after every meal for 6 days (dose administration on the first day and the sixth day being twice a day, i.e. in the morning and in the afternoon) in 12 healthy adult males has been reported in Table 4. With regard to every dose on the first day and the sixth day, the plasma concentrations showed a similar trend of change. After administration on the first day, both the Cmax and the AUC were increased in accordance with the proportional increase in the dosage quantity.

Table 4: Pharmacokinetic Parameters (n = 12)

One time dose quantity (mg)

Days of dose administration

(Total)

Cmax0-4

(µg/mL)

Tmax0-4

(hr)

Cmax4-24

(µg/mL)

Tmax4-24

(hr)

AUC0-24

(µg.hr/mL)

T1/2

(hr)

200

1

2.71 + 0.91

1.08 + 0.47

2.83 + 1.12

6.04 + 1.05

19.17 + 6.46

2.17 + 0.30

 

6

3.06  ± 1.28

1.08 + 0.82

2.70 + 0.51

6.29 + 0.96

22.03 +5.47

2.25 + 0.29

400

1 (7)

4.94 + 1.29

1.79  + 0.89

6.22 + 1.59

5.79 + 1.36

46.13 + 10.01

2.42 + 0.48

 

6 (12)

6.19 ± 1.89

1.17 + 0.54

5.91 + 2.09

6.38 + 1.15

48.69 + 11.21

2.36 + 0.38

600

1 (13)

8.20 + 1.29

1.25 +

0.45

9.21 + 1.97

6.33 +  1.15

77.22 + 15.44

2.53 + 0.42

 

6 (18)

8.19 + 1.54

1.71 +0.54

10.00 + 1.70

6.13 + 1.00

82.31 + 16.50

2.55 + 0.45

(Method of measurement: HPLC) (Mean + SD)

A reduced incidence of adverse events (nausea and dizziness) was observed in fed subjects when compared with the fasted group. Therefore, it is recommended that pirfenidone be administered after food to reduce the incidence of nausea and dizziness.

Distribution

Pirfenidone binds to human plasma proteins, primarily to serum albumin. Single oral dosing of -pirfenidone 100 mg/kg to rats indicated a higher radioactive concentrationin internal organs as compared with blood plasma.

Serum Protein-binding Rate:The serum protein-binding rate was measured by the ultra-filtration method in a healthy adult administered a single oral dose of 600 mg when fasting. After 1 hour and 3 hours of administration, the serum protein-binding was 54–62%.

Metabolism

In vitro metabolism studies with hepatic microsomes indicate that approximately 48% of pirfenidone is metabolised via CYP1A2 with other CYP isoenzymes, including CYP2C9, 2C19, 2D6 and 2E1, each contributing less than 13%. In vitro and in vivo studies to date have not detected any activity of the major metabolite (5-carboxy-pirfenidone), even at concentrations or doses greatly above those associated with activity of pirfenidone itself.

This suggests that it might not be affected by drugs that inhibit the CYP450 enzymes.

Excretion

The oral clearance of pirfenidone appears modestly saturable. In a multiple-dose, dose-ranging study in healthy older adults administered doses ranging from 267 mg to 1,335 mg three times a day, the mean clearance decreased by approximately 25% above a dose of 801 mg three times a day. Following single-dose administration of pirfenidone in healthy older adults, the mean apparent terminal elimination half-life was approximately 2.4 hours. Approximately 80% of an orally administered dose of pirfenidone is cleared inthe urine within 24 hours of dosing. The majority of pirfenidone is excreted as the 5-carboxy-pirfenidone metabolite (>95% of that recovered), with less than 1% of pirfenidone excreted unchanged in urine.

Effect of Diet

The plasma concentrations and pharmacokinetic parameters in 6 healthy adult males after a single oral administration of 400 mg after meals and when fasting are shown in

Figure 2 and Table 5. Because of the meals, the Cmax and the AUC were significantlydecreased and the Tmax was significantly delayed.

Figure 2: Plasma Concentrations after Meals and When Fasting
Table 5: Pharmacokinetic Parameters (n = 6)

Dose quantity (mg)

Cmax (µg/mL)

Tmax(hr)

AUC0-48

[µg.hr/mL)

T1/2 (hr)

400

After meal (postprandial)

4.88 + 1.72

1.83 + 0.75

22.13 + 10.63

1.77 + 0.55

Fasting

9.24 + 1.74

0.58 + 0.2

29.10 + 11.77

1.96 + 0.55

(Method of measurement: HPLC) (Mean + SD)

Special Populations

Patients with Hepatic Impairment

The pharmacokinetics of pirfenidone and the 5-carboxy-pirfenidone metabolite were compared in subjects with moderate hepatic impairment (Child-Pugh Class B) and in subjects with normal hepatic function. Results showed that there was a mean increase of 60% in pirfenidone exposure after a single dose of 801 mg pirfenidone in patients with moderate hepatic impairment. Pirfenidone should be used with caution in patients with mild-to-moderate hepatic impairment and patients should be monitored closely for signs of toxicity especially if they are concomitantly taking a known CYP1A2 inhibitor (seeRecommendations for Dose Adjustmentand SpecialWarnings and Precautions for Use).

Pirfenidone is contraindicated in severe hepatic impairment and end-stage liver disease (seeRecommendations for Dose Adjustment and Contraindications).

Patients with Renal Impairment

No clinically relevant differences in the pharmacokinetics of pirfenidone were observed insubjects with mild-to-severe renal impairment compared with subjects with normal renalfunction. The parent drug is predominantly metabolised to 5-carboxy-pirfenidone, and thepharmacokinetics of this metabolite is altered in subjects with moderate–to-severe renalimpairment. However, the predicted amount of metabolite accumulation at steady state isnot pharmacodynamically important because the terminal elimination half-life is only 1–2hours in these subjects. No dose adjustment is required in patients with mild-to-moderaterenal impairment who are receiving pirfenidone. The use of pirfenidone is contraindicatedin patients with severe renal impairment (CrCl<30mL/min) or end-stage renal diseaserequiring dialysis (see Recommendations for Dose Adjustment and Contraindications).

Population pharmacokinetic analyses from four studies in healthy subjects or subjects withrenal impairment and one study in patients with IPF showed no clinically relevant effect of age, gender or body size on the pharmacokinetics of pirfenidone.

Nonclinical Properties

Animal Toxicology or Pharmacology

Carcinogenesis

Long-term studies were conducted in mice and rats with admixture of pirfenidone to the diet to evaluate its carcinogenic potential. In a 24-month carcinogenicity study in B6C3F1 mice, pirfenidone caused statistically significant dose-related increases of the combination of hepatocellular adenoma and carcinoma and hepatoblastoma in male mice at doses of 800 mg/kg and above (AUC exposure approximately 0.4 times adult exposure at the MRDD). There were statistically significant dose-related increases of the combination of hepatocellular adenoma and carcinoma in female mice at doses of 2000 mg/kg and above (AUC exposure approximately 0.7 times adult exposure at the MRDD).

In a 24-month carcinogenicity study in Fischer rats, pirfenidone caused statistically significant dose-related increases of the combination of hepatocellular adenoma and carcinoma in male rats at doses of 750 mg/kg and above (AUC exposure approximately 1.9 times adult exposure at the MRDD). There were statistically significant increases of the combination of hepatocellular adenoma and carcinoma and the combination of uterine adenocarcinoma and adenoma at a dose of 1,500 mg/kg/day (AUC exposure approximately 3.0 times adult exposure at the MRDD). The relevance of these tumour findings in rodents to humans is unknown.

Mutagenesis

Pirfenidone was not mutagenic or clastogenic in the following tests: mutagenicity tests in bacteria, a chromosomal aberration test in Chinese hamster lung cells, and a micronucleus test in mice.

Impairment of Fertility

Pirfenidone had no effects on fertility and reproductive performance in rats at dosages up to 1,000 mg/kg/day (approximately 3 times the MRDD in adults on an mg/m2 basis).

Description

PIRFENEX belongs to the chemical class of pyridone. Pirfenidone has a molecular formula of C12H11NO and a molecular weight of 185.23

Pharmaceutical Particulars

Incompatibilities

Not applicable.

Shelf-Life

As on the pack.

Packaging Information

PIRFENEX-200: Pack of 15 tablets

PIRFENEX-400: Pack of 15 tablets

PIRFENEX-600:Pack of 15 tablets

Storage and Handling Instructions

PIRFENEX-200, PIRFENEX-400 and PIRFENEX-600

Store in a cool and dry place.

Patient Counselling Information

● What is PIRFENEX and what is it used for?

PIRFENEXtablets contain the active substance pirfenidone and they are used for the treatment of mild-to-moderate idiopathic pulmonary fibrosis (IPF) in adults. IPF is a condition in which the tissues in your lungs become swollen and scarred over time and, as a result, it becomes difficult to breathe deeply. This makes it hard for your lungs to work properly. PIRFENEX helps to reduce scarring and swelling in the lungs, and helps you breathe better.

● What you need to know before you take PIRFENEX

Do not take PIRFENEX

● if you have previously experienced angio-oedema with pirfenidone, including symptoms such as swelling of the face, lips and/or tongue, which may be associated with difficulty in breathing or wheezing

● if you are allergic to pirfenidone or any of the other ingredients of this medicine

● if you are taking a medicine called fluvoxamine ,used to treat depression and obsessive compulsive disorder (OCD)

● if you have severe or end-stage liver disease

● if you have severe or end-stage kidney disease requiring dialysis

If any of the above affects you, do not take PIRFENEX.

If you are unsure ask your doctor.

Warnings and precautions

Talk to your doctor before taking PIRFENEX:

● You may become more sensitive to sunlight (photosensitivity reaction) when taking PIRFENEX. Avoid the sun (including sunlamps) whilst taking PIRFENEX. Wear sunblock daily and cover your arms, legs and head to reduce exposure to sunlight (see section Possible side effects)

● You should not take other medicines, such as tetracycline antibiotics (such as doxycycline), which may make you more sensitive to sunlight

● You should tell your doctor if you suffer from kidney problems

● You should tell your doctor if you suffer from mild-to-moderate liver problems

● You should stop smoking before and during treatment with PIRFENEX. Cigarette smoking can reduce the effect of pirfendione

● Pirfenidone may cause dizziness and tiredness. Be careful if you have to take part in activities where you have to be alert and co-ordinated.

● Pirfenidone can cause weight loss. Your doctor will monitor your weight whilst you are taking this medicine.

You will need a blood test before you start taking PIRFENEX and at monthly intervals for the first 6 months and then every 3 months thereafter whilst you are taking this medicine to check whether your liver is working properly. It is important that you have these regular blood tests for as long as you are taking PIRFENEX.

Children and adolescents

Do not give PIRFENEX to children and adolescents under the age of 18 years.

Other medicines and PIRFENEX

Tell your doctor if you are taking, have recently taken, or might take any other medicines. This is especially important if you are taking the following medicines, as they may change the effect of PIRFENEX.

Medicines that may increase the side effects of pirfenidone

● Enoxacin (a type of antibiotic)

● Ciprofloxacin (a type of antibiotic)

● Amiodarone (used to treat some types of heart disease)

● Propafenone (used to treat some types of heart disease)

● Fluvoxamine (used to treat depression and obsessive compulsive disorder (OCD)).

Medicines that may reduce how well pirfenidone works

● Omeprazole (used in the treatment of conditions such as indigestion, gastro-oesophageal reflux disease)

● Rifampicin (a type of antibiotic)

PIRFENEX with food and drink

Do not drink grapefruit juice whilst taking this medicine. Grapefruit may prevent pirfenidone from working properly.

Pregnancy and breastfeeding

As a precautionary measure, it is preferable to avoid the use of PIRFENEX if you are pregnant, planning to become pregnant, or think you might be pregnant as the potential risks to the unborn child are unknown. If you are breastfeeding or plan to breastfeed, speak to your doctor before taking PIRFENEX.

As it is unknown whether pirfenidone passes into breast milk, your doctor will discuss the risks and benefits of taking this medicine while breastfeeding if you decide to do so.

Driving and using machines

Do not drive or use machines if you feel dizzy or tired after taking PIRFENEX.

● How to take PIRFENEX

Treatment with PIRFENEX should be started and overseen by a specialist doctor experienced in the diagnosis and treatment of IPF. Always take this medicine exactly as your doctor has told you. Check with your doctor if you are not sure.

Your medicine will usually be given to you in increasing doses as follows:

● for the first 14 days take a dose of 200 mg, three times a day with food (a total of 600 mg/day)

● from days 15 to 28 take a dose of 400 mg, three times a day with food (a total of 1,200 mg/day)

● from days 29 to 42 take a dose of 600 mg, three times a day with food (a total of 1,800 mg/day).

● from day 43 onwards, take a dose of two tablets of 400mg, three times a day with food (the recommended maintenance daily dose of PIRFENEX is 2,400 mg/day).

Swallow the tablets whole with a drink of water, during or after a meal, to reduce the risk of side effects such as nausea (feeling sick) and dizziness. If symptoms continue, see your doctor.

Dose reduction due to side effects

Your doctor may reduce your dose if you suffer from side effects such as, stomach problems, any skin reactions to sunlight or sun lamps, or significant changes in your liver enzymes.

If you take more PIRFENEX than you should

Contact your doctor immediately if you have taken more tablets than you should, and take your medicine with you.

If you forget to take PIRFENEX

If you forget a dose, take it as soon as you remember. Do not take a double dose to make up for a forgotten dose. Each dose should be separated by at least 3 hours. Do not take more tablets each day than your prescribed daily dose.

If you stop taking PIRFENEX

In some situations, your doctor may advise you to stop taking PIRFENEX. If for any reason you have to stop taking PIRFENEX for more than 14 consecutive days, your doctor will restart your treatment with a dose of 600mg/day (200 mg three times daily), gradually increasing this to a dose of 2,400 mg/day.

If you have any further questions on the use of this medicine, ask your doctor.

● What are the possible side effectsof PIRFENEX?

Like all medicines, this medicine can cause side effects, although not everybody gets them. Stop taking PIRFENEX and tell your doctor immediately

● if you experience swelling of the face, lips and/or tongue, itching, hives, difficulty breathing or wheezing, or feeling faint, which are signs of angio-oedema, a serious allergic reaction or anaphylaxis; and,

● If you experience yellowing of the eyes or skin, or dark urine, potentially accompanied by itching of the skin, which are signs of abnormal liver function tests. These are rare side effects.

Talk to your doctor if you get any side effects.

Very common side effects (may affect more than 1 in 10 people)

● Skin reactions after going out in the sun or using sunlamps

● Feeling sick (nausea)

● Tiredness

● Diarrhoea

● Indigestion or stomach upset

● Loss of appetite

● Headache

Common side effects (may affect up to 1 in 10 people)

● Infections of the throat or the airways going into the lungs and/or sinusitis

● Bladder infections

● Weight loss

● Difficulty sleeping

● Dizziness

● Feeling sleepy

● Changes in taste

● Hot flushes

● Shortness of breath

● Cough

● Stomach problems such as acid reflux, vomiting, feeling bloated, abdominal pain and discomfort, heartburn, feeling constipated and passing wind

● Blood tests may show increased levels of liver enzymes

● Skin problems such as itchy skin, skin redness or red skin, dry skin, skin rash

● Muscle pain, aching joints/joint pains

● Feeling weak or feeling low in energy

● Chest pain

● Sunburn

Rare side effects (may affect up to 1 in 1,000 people)

● Blood tests may show decrease in white blood cells

Reporting of side effects

If you experience any side effects, including any possible side effects not listed in this leaflet, talk to your doctor or pharmacist or write to drugsafety@cipla.com. You can also report side effects directly via the National Pharmacovigilance Programme of India by calling on 1800 180 3024 or you can report to Cipla Ltd. on 1800 267 7779. By reporting side effects, you can help provide more information on the safety of this product.

Details of The Manufacturer

Mfd. by Cipla Ltd.

Regd. Office:Cipla House, Peninsula Business Park,

Ganpatrao Kadam Marg,Lower Parel,Mumbai – 400 013, India

Details of Permission or Licence Number with Date

200mg;M/719/2016 dated 10/06/2017

400mg; MNB/05/109 dated 12/09/2019

600mg; MNB/05/109 & MB/05/110 dated 14/01/2020

Date of Revision

21/01/2020