Pirfenidone Tablets 400mg Taj Pharma

Pirfenidone Tablets 400mg Taj Pharma

1. Name of the medicinal product

Pirfenidone 200mg film-coated tablets Taj Pharma
Pirfenidone 400mg film-coated tablets Taj Pharma

2. Qualitative and quantitative composition

Each film-coated tablet contains
Pirfenidone                        200mg
Excipients                           qs

Each film-coated tablet contains
Pirfenidone                        400mg
Excipients                           qs
For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Film-coated tablet.

4. Clinical particulars

4.1 Therapeutic indications

Pirfenidone is indicated in adults for the treatment of mild to moderate idiopathic pulmonary fibrosis (IPF).

4.2 Posology and method of administration

Treatment with Pirfenidone should be initiated and supervised by specialist physicians experienced in the diagnosis and treatment of IPF.

Posology

Adults

Upon initiating treatment, the dose should be titrated to the recommended daily dose of 2403mg/day over a 14-day period as follows:

• Days 1 to 7: a dose of 200mg administered three times a day (801mg/day)
• Days 8 to 14: a dose of 534mg administered three times a day (1602mg/day)
• Day 15 onward: a dose of 801mg administered three times a day (2403mg/day)

The recommended maintenance daily dose of Pirfenidone is 801mg three times a day with food for a total of 2403mg/day.

Doses above 2403mg/day are not recommended for any patient (see section 4.9).

Patients who miss 14 consecutive days or more of Pirfenidone treatment should re-initiate therapy by undergoing the initial 2-week 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 undesirable effects, patients should be reminded to take the medicinal product with food. If symptoms persist, the dose of pirfenidone may be reduced to 200mg – 534mg, two to three times a day with food with re-escalation to the recommended daily dose as tolerated. If symptoms continue, patients may be instructed to interrupt treatment for one to two weeks to allow symptoms to resolve.

Photosensitivity reaction or rash: Patients who experience a mild to moderate photosensitivity reaction or rash should be reminded to use a sunblock daily and avoid exposure to the sun (see section 4.4). The dose of pirfenidone may be reduced to 801mg each day (200mg three times a day). If the rash persists after 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 (see section 4.4). 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.

Hepatic function: In the event of significant elevation of alanine and/or aspartate aminotransferases (ALT/AST) with or without bilirubin elevation, the dose of pirfenidone should be adjusted or treatment discontinued according to the guidelines listed in section 4.4.

Special populations

Elderly

No dose adjustment is necessary in patients 65 years and older (see section 5.2).

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. Pirfenidone therapy should not be used in patients with severe hepatic impairment or end stage liver disease (see section 4.3, 4.4 and 5.2).

Renal impairment

No dose adjustment is necessary in patients with mild renal impairment. Pirfenidone should be used with caution in patients with moderate (CrCl 30-50 ml/min) renal impairment. Pirfenidone therapy should not be used in patients with severe renal impairment (CrCl <30 ml/min) or end stage renal disease requiring dialysis (see sections 4.3 and 5.2).

Paediatric population

There is no relevant use of Pirfenidone in the paediatric population for the indication of IPF.

Method of administration

Pirfenidone is for oral use. The tablets are to be swallowed whole with water and taken with food to reduce the possibility of nausea and dizziness (see sections 4.8 and 5.2).

4.3 Contraindications

• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
• History of angioedema with pirfenidone (see section 4.4).
• Concomitant use of fluvoxamine (see section 4.5).
• Severe hepatic impairment or end stage liver disease (see sections 4.2 and 4.4).
• Severe renal impairment (CrCl <30 ml/min) or end stage renal disease requiring dialysis (see sections 4.2 and 5.2).

4.4 Special warnings and precautions for use

Hepatic function

Elevations in ALT and AST >3 × upper limit of normal (ULN) have been reported in patients receiving therapy with Pirfenidone. Rarely these have been associated with concomitant elevations in total serum bilirubin. Liver function tests (ALT, AST and bilirubin) should be conducted prior to the initiation of treatment with Pirfenidone, and subsequently at monthly intervals for the first 6 months and then every 3 months thereafter (see section 4.8). In the event of significant elevation of liver aminotransferases the dose of Pirfenidone should be adjusted or treatment discontinued according to the guidelines listed below. For patients with confirmed elevations in ALT, AST or bilirubin during treatment, the following dose adjustments may be necessary.

Recommendations in case of ALT/AST elevations

If a patient exhibits an aminotransferase elevation to >3 to ≤5 x 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.

Hepatic impairment

In subjects with moderate hepatic impairment (i.e. Child-Pugh Class B), pirfenidone exposure was increased by 60%. Pirfenidone should be used with caution in patients with pre-existing mild to moderate hepatic impairment (i.e. Child-Pugh Class A and B) given the potential for increased pirfenidone exposure. Patients should be monitored closely for signs of toxicity especially if they are concomitantly taking a known CYP1A2 inhibitor (see sections 4.5 and 5.2). Pirfenidone has not been studied in individuals with severe hepatic impairment and Pirfenidone must not be used in patients with severe hepatic impairment (see section 4.3).

Photosensitivity reaction and rash

Exposure to direct sunlight (including sunlamps) should be avoided or minimised during treatment with Pirfenidone. Patients should be instructed to use a sunblock daily, to wear clothing that protects against sun exposure, and to avoid other medicinal products known to cause photosensitivity. Patients should be instructed to report symptoms of photosensitivity reaction or rash to their physician. Severe photosensitivity reactions are uncommon. Dose adjustments or temporary treatment discontinuation may be necessary in mild to severe cases of photosensitivity reaction or rash (see section 4.2).

Angioedema/Anaphylaxis

Reports of angioedema (some serious) such as swelling of the face, lips and/or tongue which may be associated with difficulty breathing or wheezing have been received in association with use of Pirfenidone in the post-marketing setting. Reports of anaphylactic reactions have also been received. Therefore, patients who develop signs or symptoms of angioedema or severe allergic reactions following administration of Pirfenidone should immediately discontinue treatment. Patients with angioedema or severe allergic reactions should be managed according to standard of care. Pirfenidone must not be used in patients with a history of angioedema or hypersensitivity due to Pirfenidone (see section 4.3).

Dizziness

Dizziness has been reported in patients taking Pirfenidone. Therefore, patients should know how they react to this medicinal product before they engage in activities requiring mental alertness or coordination (see section 4.7). In clinical studies, most patients who experienced dizziness had a single event, and most events resolved, with a median duration of 22 days. If dizziness does not improve or if it worsens in severity, dose adjustment or even discontinuation of Pirfenidone may be warranted.

Fatigue

Fatigue has been reported in patients taking Pirfenidone. Therefore, patients should know how they react to this medicinal product before they engage in activities requiring mental alertness or coordination (see section 4.7).

Weight loss

Weight loss has been reported in patients treated with Pirfenidone (see section 4.8). Physicians should monitor patient’s weight, and when appropriate encourage increased caloric intake if weight loss is considered to be of clinical significance.

4.5 Interaction with other medicinal products and other forms of interaction

Approximately 70–80% of pirfenidone is metabolised via CYP1A2 with minor contributions from other CYP isoenzymes including CYP2C9, 2C19, 2D6, and 2E1.

Consumption of grapefruit juice is associated with inhibition of CYP1A2 and should be avoided during treatment with pirfenidone.

Fluvoxamine and inhibitors of CYP1A2

In a Phase 1 study, the co-administration of Pirfenidone and fluvoxamine (a strong inhibitor of CYP1A2 with inhibitory effects on other CYP isoenzymes [CYP2C9, 2C19, and 2D6]) resulted in a 4-fold increase in exposure to pirfenidone in non-smokers.

Pirfenidone is contraindicated in patients with concomitant use of fluvoxamine (see section 4.3). Fluvoxamine should be discontinued prior to the initiation of Pirfenidone therapy and avoided during Pirfenidone therapy due to the reduced clearance of pirfenidone. Other therapies that are inhibitors of both CYP1A2 and one or more other CYP isoenzymes involved in the metabolism of pirfenidone (e.g. CYP2C9, 2C19, and 2D6) should be avoided during pirfenidone treatment.

In vitro and in vivo extrapolations indicate that strong and selective inhibitors of CYP1A2 (e.g. enoxacin) have the potential to increase the exposure to pirfenidone by approximately 2 to 4-fold. If concomitant use of Pirfenidone with a strong and selective inhibitor of CYP1A2 cannot be avoided, the dose of pirfenidone should be reduced to 801mg daily (200mg, three times a day). Patients should be closely monitored for emergence of adverse reactions associated with Pirfenidone therapy. Discontinue Pirfenidone if necessary (see sections 4.2 and 4.4).

Co-administration of Pirfenidone and 750mg of ciprofloxacin (a moderate inhibitor of CYP1A2) increased the exposure to pirfenidone by 81%. If ciprofloxacin at the dose of 750mg two times a day cannot be avoided, the dose of pirfenidone should be reduced to 1602mg daily (534mg, three times a day). Pirfenidone should be used with caution when ciprofloxacin is used at a dose of 250mg or 500mg once or two times a day.

Pirfenidone should be used with caution in patients treated with other moderate inhibitors of CYP1A2 (e.g. amiodarone, propafenone).

Special care should also be exercised if CYP1A2 inhibitors are being used concomitantly with potent inhibitors of one or more other CYP isoenzymes involved in the metabolism of pirfenidone such as CYP2C9 (e.g. amiodarone, fluconazole), 2C19 (e.g. chloramphenicol) and 2D6 (e.g. fluoxetine, paroxetine).

Cigarette smoking and inducers of CYP1A2

A Phase 1 interaction study evaluated the effect of cigarette smoking (CYP1A2 inducer) on the pharmacokinetics of pirfenidone. The exposure to pirfenidone in smokers was 50% of that observed in non-smokers. Smoking has the potential to induce hepatic enzyme production and thus increase medicinal product clearance and decrease exposure. Concomitant use of strong inducers of CYP1A2 including smoking should be avoided during Pirfenidone therapy based on the observed relationship between cigarette smoking and its potential to induce CYP1A2. Patients should be encouraged to discontinue use of strong inducers of CYP1A2 and to stop smoking before and during treatment with pirfenidone.

In the case of moderate inducers of CYP1A2 (e.g. omeprazole), concomitant use may theoretically result in a lowering of pirfenidone plasma levels.

Co-administration of medicinal products that act as potent inducers of both CYP1A2 and the other CYP isoenzymes involved in the metabolism of pirfenidone (e.g. rifampicin) may result in significant lowering of pirfenidone plasma levels. These medicinal products should be avoided whenever possible.

4.6 Fertility, pregnancy and lactation

Pregnancy

There are no data from the use of Pirfenidone in pregnant women.

In animals placental transfer of pirfenidone and/or its metabolites occurs with the potential for accumulation of pirfenidone and/or its metabolites in amniotic fluid.

At high doses (≥1,000mg/kg/day) rats exhibited prolongation of gestation and reduction in foetal viability.

As a precautionary measure, it is preferable to avoid the use of Pirfenidone during pregnancy.

Breast-feeding

It is unknown whether pirfenidone or its metabolites are excreted in human milk. Available pharmacokinetic data in animals have shown excretion of pirfenidone and/or its metabolites in milk with the potential for accumulation of pirfenidone and/or its metabolites in milk (see section 5.3). A risk to the breastfed infant cannot be excluded.

A decision must be made whether to discontinue breast-feeding or to discontinue from Pirfenidone therapy, taking into account the benefit of breast-feeding for the child and the benefit of Pirfenidone therapy for the mother.

Fertility

No adverse effects on fertility were observed in preclinical studies (see section 5.3).

4.7 Effects on ability to drive and use machines

Pirfenidone may cause dizziness and fatigue, which could have a moderate influence on the ability to drive or use machines, therefore patients should exercise caution when driving or operating machinery if they experience these symptoms.

4.8 Undesirable effects

Summary of the safety profile

The most frequently reported adverse reactions during clinical study experience with Pirfenidone at a dose of 2,403mg/day compared to placebo, respectively, were nausea (32.4% versus 12.2%), rash (26.2% versus 7.7%), diarrhoea (18.8% versus 14.4%), fatigue (18.5% versus 10.4%), dyspepsia (16.1% versus 5.0%), anorexia (11.4% versus 3.5%), headache (10.1% versus 7.7%), and photosensitivity reaction (9.3% versus 1.1%).

Tabulated list of adverse reactions

The safety of Pirfenidone has been evaluated in clinical studies including 1,650 volunteers and patients. More than 170 patients have been investigated in open studies for more than five years and some for up to 10 years.

Table 1 shows the adverse reactions reported at a frequency of ≥2% in 623 patients receiving Pirfenidone at the recommended dose of 2,403mg/day in three pooled pivotal Phase 3 studies. Adverse reactions from post-marketing experience are also listed in Table 1. Adverse reactions are listed by System Organ Class (SOC) and within each frequency grouping [Very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), not known (cannot be estimated from the available data)] the adverse reactions are presented in order of decreasing seriousness.

1. Identified through post-marketing surveillance

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.

4.9 Overdose

There is limited clinical experience with overdose. Multiple doses of pirfenidone up to a total dose of 4,806mg/day were administered as six 200mg 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.

5. Pharmacological properties

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Immunosuppressants, other immunosuppressants.

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).

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).

Clinical efficacy

The clinical efficacy of Pirfenidone has been studied in four Phase 3, multicentre, randomised, double-blind, placebo-controlled studies in patients with IPF. Three of the Phase 3 studies (PIPF-004, PIPF-006, and PIPF-016) were multinational, and one (SP3) was conducted in Japan.

PIPF-004 and PIPF-006 compared treatment with Pirfenidone 2403mg/day to placebo. The studies were nearly identical in design, with few exceptions including an intermediate dose group (1,197mg/day) in PIPF-004. In both studies, treatment was administered three times daily for a minimum of 72 weeks. The primary endpoint in both studies was the change from Baseline to Week 72 in percent predicted Forced Vital Capacity (FVC).

In study PIPF-004, the decline of percent predicted FVC from Baseline at Week 72 of treatment was significantly reduced in patients receiving Pirfenidone (N=174) compared with patients receiving placebo (N=174; p=0.001, rank ANCOVA). Treatment with Pirfenidone also significantly reduced the decline of percent predicted FVC from Baseline at Weeks 24 (p=0.014), 36 (p<0.001), 48 (p<0.001), and 60 (p<0.001). At Week 72, a decline from baseline in percent predicted FVC of ≥10% (a threshold indicative of the risk of mortality in IPF) was seen in 20% of patients receiving Pirfenidone compared to 35% receiving placebo (Table 2).

Although there was no difference between patients receiving Pirfenidone compared to placebo in change from Baseline to Week 72 of distance walked during a six minute walk test (6MWT) by the prespecified rank ANCOVA, in an ad hoc analysis, 37% of patients receiving Pirfenidone showed a decline of ≥50 m in 6MWT distance, compared to 47% of patients receiving placebo in PIPF-004.

In study PIPF-006, treatment with Pirfenidone (N=171) did not reduce the decline of percent predicted FVC from Baseline at Week 72 compared with placebo (N=173; p=0.501). However, treatment with Pirfenidone reduced the decline of percent predicted FVC from Baseline at Weeks 24 (p<0.001), 36 (p=0.011), and 48 (p=0.005). At Week 72, a decline in FVC of ≥10% was seen in 23% of patients receiving Pirfenidone and 27% receiving placebo (Table 3).

The decline in 6MWT distance from Baseline to Week 72 was significantly reduced compared with placebo in study PIPF-006 (p<0.001, rank ANCOVA). Additionally, in an ad hoc analysis, 33% of patients receiving Pirfenidone showed a decline of ≥50 m in 6MWT distance, compared to 47% of patients receiving placebo in PIPF-006.

In a pooled analysis of survival in PIPF-004 and PIPF-006 the mortality rate with Pirfenidone 2403mg/day group was 7.8% compared with 9.8% with placebo (HR 0.77 [95% CI, 0.47–1.28]).

PIPF-016 compared treatment with Pirfenidone 2,403mg/day to placebo. Treatment was administered three times daily for 52 weeks. The primary endpoint was the change from Baseline to Week 52 in percent predicted FVC. In a total of 555 patients, the median baseline percent predicted FVC and %DL_CO were 68% (range: 48–91%) and 42% (range: 27–170%), respectively. Two percent of patients had percent predicted FVC below 50% and 21% of patients had a percent predicted DL_CO below 35% at Baseline.

In study PIPF-016, the decline of percent predicted FVC from Baseline at Week 52 of treatment was significantly reduced in patients receiving Pirfenidone (N=278) compared with patients receiving placebo (N=277; p<0.000001, rank ANCOVA). Treatment with Pirfenidone also significantly reduced the decline of percent predicted FVC from Baseline at Weeks 13 (p<0.000001), 26 (p<0.000001), and 39 (p=0.000002). At Week 52, a decline from Baseline in percent predicted FVC of ≥10% or death was seen in 17% of patients receiving Pirfenidone compared to 32% receiving placebo (Table 4).

The decline in distance walked during a 6MWT from Baseline to Week 52 was significantly reduced in patients receiving Pirfenidone compared with patients receiving placebo in PIPF-016 (p=0.036, rank ANCOVA); 26% of patients receiving Pirfenidone showed a decline of ≥50 m in 6MWT distance compared to 36% of patients receiving placebo.

In a pre-specified pooled analysis of studies PIPF-016, PIPF-004, and PIPF-006 at Month 12, all-cause mortality was significantly lower in Pirfenidone 2403mg/day group (3.5%, 22 of 623 patients) compared with placebo (6.7%, 42 of 624 patients), resulting in a 48% reduction in the risk of all-cause mortality within the first 12 months (HR 0.52 [95% CI, 0.31–0.87], p=0.0107, log-rank test).

The study (SP3) in Japanese patients compared pirfenidone 1800mg/day (comparable to 2403mg/day in the US and European populations of PIPF-004/006 on a weight-normalised basis) with placebo (N=110, N=109, respectively). Treatment with pirfenidone significantly reduced mean decline in vital capacity (VC) at Week 52 (the primary endpoint) compared with placebo (-0.09±0.02 l versus -0.16±0.02 l respectively, p=0.042).

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with Pirfenidone in all subsets of the paediatric population in IPF (see section 4.2 for information on paediatric use).

5.2 Pharmacokinetic properties

Absorption

Administration of Pirfenidone capsules with food results in a large reduction in Cmax (by 50%) and a smaller effect on AUC, compared to the fasted state. Following oral administration of a single dose of 801mg to healthy older adult volunteers (50-66 years of age) in the fed state, the rate of pirfenidone absorption slowed, while the AUC in the fed state was approximately 80-85% of the AUC observed in the fasted state. Bioequivalence was demonstrated in the fasted state when comparing the 801mg tablet to three 200mg capsules. In the fed state, the 801mg tablet met bioequivalence criteria based on the AUC measurements compared to the capsules, while the 90% confidence intervals for Cmax (108.26% – 125.60%) slightly exceeded the upper bound of standard bioequivalence limit (90% CI: 80.00% – 125.00%). The effect of food on pirfenidone oral AUC was consistent between the tablet and capsule formulations. Compared to the fasted state, administration of either formulation with food reduced pirfenidone Cmax, with Pirfenidone tablet reducing the Cmax slightly less (by 40%) than Pirfenidone capsules (by 50%). A reduced incidence of adverse events (nausea and dizziness) was observed in fed subjects when compared to the fasted group. Therefore, it is recommended that Pirfenidone be administered with food to reduce the incidence of nausea and dizziness.

The absolute bioavailability of pirfenidone has not been determined in humans.

Distribution

Pirfenidone binds to human plasma proteins, primarily to serum albumin. The overall mean binding ranged from 50% to 58% at concentrations observed in clinical studies (1 to 100 μg/ml). Mean apparent oral steady-state volume of distribution is approximately 70 l, indicating that pirfenidone distribution to tissues is modest.

Biotransformation

Approximately 70–80% of pirfenidone is metabolised via CYP1A2 with minor contributions from other CYP isoenzymes including CYP2C9, 2C19, 2D6, and 2E1. In vitro data indicate some pharmacologically relevant activity of the major metabolite (5-carboxy-pirfenidone) at concentrations in excess of peak plasma concentrations in IPF patients. This may become clinically relevant in patients with moderate renal impairment where plasma exposure to 5-carboxy-pirfenidone is increased

Elimination

The oral clearance of pirfenidone appears modestly saturable. In a multiple-dose, dose-ranging study in healthy older adults administered doses ranging from 200mg to 1,335mg three times a day, the mean clearance decreased by approximately 25% above a dose of 801mg 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 in the 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.

Special populations

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 801mg pirfenidone (3 x 200mg capsule) 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 (see sections 4.2 and 4.4). Pirfenidone is contraindicated in severe hepatic impairment and end stage liver disease (see sections 4.2 and 4.3).

Renal impairment

No clinically relevant differences in the pharmacokinetics of pirfenidone were observed in subjects with mild to severe renal impairment compared with subjects with normal renal function. The parent substance is predominantly metabolised to 5-carboxy-pirfenidone. The mean (SD) AUC0-∞ of 5-carboxy-pirfenidone was significantly higher in the moderate (p = 0.009) and severe (p < 0.0001) renal impairment groups than in the group with normal renal function; 100 (26.3)mg•h/L and 168 (67.4)mg•h/L compared to 28.7 (4.99)mg•h/L respectively.

AUC_0-∞ = area under the concentration-time curve from time zero to infinity.

^a p-value versus Normal = 1.00 (pair-wise comparison with Bonferroni)

^b p-value versus Normal = 0.009 (pair-wise comparison with Bonferroni)

^c p-value versus Normal < 0.0001 (pair-wise comparison with Bonferroni)

Exposure to 5-carboxy-pirfenidone increases 3.5 fold or more in patients with moderate renal impairment. Clinically relevant pharmacodynamic activity of the metabolite in patients with moderate renal impairment cannot be excluded. No dose adjustment is required in patients with mild renal impairment who are receiving pirfenidone. Pirfenidone should be used with caution in patients with moderate renal impairment. The use of pirfenidone is contraindicated in patients with severe renal impairment (CrCl <30ml/min) or end stage renal disease requiring dialysis (see sections 4.2 and 4.3).

Population pharmacokinetic analyses from 4 studies in healthy subjects or subjects with renal impairment and one study in patients with IPF showed no clinically relevant effect of age, gender or body size on the pharmacokinetics of pirfenidone.

5.3 Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential.

In repeated dose toxicity studies increases in liver weight were observed in mice, rats and dogs; this was often accompanied by hepatic centrilobular hypertrophy. Reversibility was observed after cessation of treatment. An increased incidence of liver tumours was observed in carcinogenicity studies conducted in rats and mice. These hepatic findings are consistent with an induction of hepatic microsomal enzymes, an effect which has not been observed in patients receiving Pirfenidone. These findings are not considered relevant to humans.

A statistically significant increase in uterine tumours was observed in female rats administered 1,500mg/kg/day, 37 times the human dose of 2,403mg/day. The results of mechanistic studies indicate that the occurrence of uterine tumours is probably related to a chronic dopamine-mediated sex hormone imbalance involving a species specific endocrine mechanism in the rat which is not present in humans.

Reproductive toxicology studies demonstrated no adverse effects on male and female fertility or postnatal development of offspring in rats and there was no evidence of teratogenicity in rats (1,000mg/kg/day) or rabbits (300mg/kg/day). In animals placental transfer of pirfenidone and/or its metabolites occurs with the potential for accumulation of pirfenidone and/or its metabolites in amniotic fluid. At high doses (≥450mg/kg/day) rats exhibited a prolongation of oestrous cycle and a high incidence of irregular cycles. At high doses (≥1,000mg/kg/day) rats exhibited a prolongation of gestation and reduction in fetal viability. Studies in lactating rats indicate that pirfenidone and/or its metabolites are excreted in milk with the potential for accumulation of pirfenidone and/or its metabolites in milk.

Pirfenidone showed no indication of mutagenic or genotoxic activity in a standard battery of tests and when tested under UV exposure was not mutagenic. When tested under UV exposure pirfenidone was positive in a photoclastogenic assay in Chinese hamster lung cells.

Phototoxicity and irritation were noted in guinea pigs after oral administration of pirfenidone and with exposure to UVA/UVB light. The severity of phototoxic lesions was minimised by application of sunscreen.

6. Pharmaceutical particulars

6.1 List of excipients

Tablet core

Microcrystalline cellulose, Croscarmellose sodium, Povidone K30

Colloidal anhydrous silica, Magnesium stearate

Film coat

Polyvinyl alcohol, Titanium dioxide, Macrogol 3350, Talc

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years for blisters.

4 years for bottles.

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

High-Density Polyethylene (HDPE) bottle with a child-resistant and tamper-evident screw cap

Pack sizes

200mg film-coated tablets

Bottle containing 21, 42, 90, 180 film-coated tablets

200mg film-coated tablets

Blister containing 21, 42, 84, 168 film-coated tablets

2-week treatment initiation pack: multipack containing 63 (1 pack containing 1 blister of 21 and 1 pack containing 2 blisters of 21) film-coated tablets

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

1. 7. Manufactured in India by:
      TAJ PHARMACEUTICALS LTD.
      Mumbai, India
      Unit No. 214.Old Bake House,
      Maharashtra chambers of Commerce Lane,
      Fort, Mumbai – 400001
      at:Gujarat, INDIA.
      Customer Service and Product Inquiries:
      1-800-TRY-FIRST (1-800-222-434 & 1-800-222-825)
      Monday through Saturday 9:00 a.m. to 7:00 p.m. EST
      E-mail: tajgroup@tajpharma.com.

Pirfenidone Tablets 200mg, 400mg Taj Pharma

Package leaflet: Information for the user Pirfenidone 200mg film-coated tablets Pirfenidone 400mg film-coated tablets
Pirfenidone

Read all of this leaflet carefully before you start taking this medicine because it contains important information for you.

Keep this leaflet. You may need to read it again.

• If you have any further questions, ask your doctor or
• This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.
• If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. See section

What is in this leaflet

1. What Pirfenidone is and what it is used for
2. What you need to know before you take Pirfenidone
3. How to take Pirfenidone
4. Possible side effects

5          How to store Pirfenidone

6. Contents of the pack and other information

1               What Pirfenidone is and what it is used for

Pirfenidone contains the active substance pirfenidone and it is 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 makes it difficult to breathe deeply. This makes it hard for your lungs to work properly. Pirfenidone helps to reduce scarring and swelling in the lungs, and helps you breathe better.

What you need to know before you take Pirfenidone Do not take Pirfenidone

• if you are allergic to pirfenidone or any of the other ingredients of this medicine (listed in section 6)
• if you have previously experienced angioedema with pirfenidone, including symptoms such as swelling of the face, lips and/or tongue which may be associated with difficulty breathing or wheezing
• 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 Pirfenidone. If you are unsure ask your doctor or pharmacist.

Warnings and precautions

Talk to your doctor or pharmacist before taking Pirfenidone

• You may become more sensitive to sunlight (photosensitivity reaction) when taking Pirfenidone. Avoid the sun (including sunlamps) whilst taking Pirfenidone. Wear sunblock daily and cover your arms, legs and head to reduce exposure to sunlight (see section 4: 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
• You should stop smoking before and during treatment with Pirfenidone. Cigarette smoking can reduce the effect of
• 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 Pirfenidone 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 Pirfenidone.

Children and adolescents

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

Other medicines and Pirfenidone

Tell your doctor or pharmacist 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 Pirfenidone.

Medicines that may increase 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, gastroesophageal reflux disease)
• rifampicin (a type of antibiotic).

Pirfenidone with food and drink

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

Pregnancy and breast-feeding

As a precautionary measure, it is preferable to avoid the use of Pirfenidone 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 breast-feeding or plan to breast-feed speak to your doctor or pharmacist before taking Pirfenidone. As it is unknown whether Pirfenidone passes into breast milk, your doctor will discuss the risks and benefits of taking this medicine while breast-feeding if you decide to do so.

Driving and using machines

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

3       How to take Pirfenidone

Treatment with Pirfenidone 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 or pharmacist has told you. Check with your doctor or pharmacist if you are not sure.

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

• for the first 7 days take a dose of 200mg (1 yellow tablet), 3 times a day with food (a total of 801mg/day)
• from day 8 to 14 take a dose of 400mg (2 yellow tablets or 1 orange tablet), 3 times a day with food (a total of 1,602mg/day)
• from day 15 onwards (maintenance), take a dose of 801mg (3 yellow tablets or 1 brown tablet), 3 times a day with food (a total of 2,403mg/day).

The recommended maintenance daily dose of Pirfenidone is 801mg (3 yellow tablets or 1 brown tablet) three times a day with food, for a total of 2403mg/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 to your liver enzymes.

If you take more Pirfenidone than you should

Contact your doctor, pharmacist or nearest hospital casualty department immediately if you have taken more tablets than you should, and take your medicine with you.

If you forget to take Pirfenidone

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 Pirfenidone

In some situations, your doctor may advise you to stop taking Pirfenidone. If for any reason you have to stop taking Pirfenidone for more than 14 consecutive days, your doctor will restart your treatment with a dose of 200mg 3 times a day, gradually increasing this to a dose of 801mg 3 times a day.

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

4.              Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them. Stop taking Pirfenidone 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 angioedema, a serious allergic reaction or anaphylaxis.

• 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

Other side effects may include

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

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, heart burn, 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

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

• blood tests may show decrease in white blood

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet.

5.             How to store Pirfenidone

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the bottle label, blister and carton after EXP. The expiry date refers to the last day of that month.

This medicine does not require any special storage conditions.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

6. Contents of the pack and other information What Pirfenidone contains

200mg tablet

The active substance is pirfenidone. Each film-coated tablet contains 200mg of pirfenidone.

The other ingredients are: microcrystalline cellulose, croscarmellose sodium, povidone K30, colloidal anhydrous silica, magnesium stearate

The film coat consists of: polyvinyl alcohol, titanium dioxide (E171), macrogol 3350, talc, iron oxide yellow (E172)

400mg tablet

The active substance is pirfenidone. Each film-coated tablet contains 400mg of pirfenidone.

The other ingredients are: microcrystalline cellulose, croscarmellose sodium, povidone K30, colloidal anhydrous silica, magnesium stearate

The film coat consists of: polyvinyl alcohol, titanium dioxide, macrogol 3350, talc, iron oxide yellow and iron oxide red

What Pirfenidone looks like and contents of the pack

200mg tablet

Pirfenidone 200mg film-coated tablets

The bottle packs contain one bottle containing 21 tablets, two bottles each containing 21 tablets (42 tablets in total), one bottle containing 42 tablets, one bottle containing 90 tablets, two bottles each containing 90 tablets (180 tablets in total) or one bottle containing 180 tablets.

The blister packs contain 21, 42, 84 or 168 film-coated tablets and the multipacks contain 63 (2-week treatment initiation pack 21+42) or 252 (continuation pack 3×84) film-coated tablets.

Not all pack sizes may be marketed.

1. 7. Manufactured in India by:
      TAJ PHARMACEUTICALS LTD.
      Mumbai, India
      Unit No. 214.Old Bake House,
      Maharashtra chambers of Commerce Lane,
      Fort, Mumbai – 400001
      at:Gujarat, INDIA.
      Customer Service and Product Inquiries:
      1-800-TRY-FIRST (1-800-222-434 & 1-800-222-825)
      Monday through Saturday 9:00 a.m. to 7:00 p.m. EST
      E-mail: tajgroup@tajpharma.com