Patizra

Sterile, clear, colourless to pale yellow to brown and preservative-free aqueous solution.
One mL contains 10 mg ranibizumab.
Each vial contains 2.3 mg of ranibizumab in 0.23 mL solution.
Ranibizumab is a humanized monoclonal antibody fragment produced in Escherichia coli cells by recombinant DNA technology.
Excipients/Inactive Ingredients: Alpha, alpha-trehalose dihydrate, histidine hydrochloride, monohydrate, histidine, polysorbate 20, water for injection.

Pharmacotherapeutic group: Antineovascularisation agents. ATC code: S01LA04.
Pharmacology: Mechanism of action (MOA): Ranibizumab is a humanized recombinant monoclonal antibody fragment targeted against human vascular endothelial growth factor A (VEGF-A). It binds with high affinity to the VEGF-A isoforms (e.g. VEGF₁₁₀, VEGF₁₂₁ and VEGF₁₆₅), thereby preventing binding of VEGF-A to its receptors VEGFR-1 and VEGFR-2.
Pharmacodynamics (PD): Binding of VEGF A to its receptors leads to endothelial cell proliferation and neovascularisation, as well as vascular leakage, which are thought to contribute to the progression of the neovascular form of age-related macular degeneration, to the development of CNV secondary to pathologic myopia, or to the macular edema causing visual impairment in diabetes and retinal vein occlusion.
Pharmacokinetics (PK): Absorption: Following monthly intravitreal administration of Patizra to patients with neovascular AMD, serum concentrations of ranibizumab were generally low, with maximum levels (C_max) generally below the ranibizumab concentration necessary to inhibit the biological activity of VEGF by 50% (11 to 27 ng/mL, as assessed in an in vitro cellular proliferation assay). C_max was dose proportional over the dose range of 0.05 to 1.0 mg/eye. Upon monthly intravitreal administration of Patizra 0.5 mg/eye, serum ranibizumab C_max, attained approximately 1 day after dosing, is predicted to generally range between 0.79 and 2.90 ng/mL, and C_min is predicted to generally range between 0.07 and 0.49 ng/mL. Serum rabinizumab concentrations in DME and RVO patients were similar to those observed in neovascular AMD patients.
Distribution and elimination: Based on analysis of population pharmacokinetics and disappearance of ranibizumab from serum for patients with neovascular AMD treated with the 0.5 mg dose, the average vitreous elimination half-life of ranibizumab is approximately 9 days. Serum ranibizumab exposure is predicted to be approximately 90,000-fold lower than vitreal ranibizumab exposure.
Special populations: Pediatric Population (preterm infants with ROP): Following intravitreal administration of ranibizumab to preterm infants with ROP at a dose of 0.2 mg (per eye), serum ranibizumab concentrations were higher than those observed in neovascular AMD adult patients receiving 0.5 mg in one eye. Based on a population pharmacokinetic analysis, the differences in C_max and AUC_inf were approximately 16-fold and 12-fold higher, respectively. The apparent systemic half-life was approximately 6 days. In this analysis, there was no relationship determined between systemic ranibizumab concentrations and systemic VEGF concentrations.
Renal impairment: No formal studies have been conducted to examine the pharmacokinetics of Patizra in patients with renal impairment. In a population pharmacokinetic analysis of neovascular AMD, 68% (136 of 200) had renal impairment (46.5% mild [50 to 80 mL/min], 20% moderate [30 to 50 mL/min] and 1.5% severe [<30 mL/min]). In RVO patients, 48.2% (253 of 525) had renal impairment (36.4% mild, 9.5% moderate and 2.3% severe). Systemic clearance was slightly lower, but this was not clinically significant.
Hepatic impairment: No formal studies have been conducted to examine the pharmacokinetics of Patizra in patients with hepatic impairment.
Clinical Studies: Treatment of wet AMD: In wet AMD, the clinical safety and efficacy of ranibizumab have been assessed in three randomized, double-masked, sham**- or active-controlled studies in patients with neovascular AMD (FVF2598g (MARINA), FVF2587g (ANCHOR) and FVF3192g (PIER)). A total of 1,323 patients (879 active and 444 control) were enrolled in these studies.
Study FVF2598g (MARINA) and study FVF2587g (ANCHOR): In the 24-month study FVF2598g (MARINA), patients with minimally classic or occult with no classic CNV received monthly intravitreal injections of ranibizumab 0.3 mg or 0.5 mg or sham injections. A total of 716 patients were enrolled in this study (sham, 238; Patizra 0.3 mg, 238; ranibizumab 0.5 mg, 240).
In the 24-month study FVF2587g (ANCHOR), patients with predominantly classic CNV lesions received either: monthly intravitreal injections of ranibizumab 0.3 mg and sham PDT; monthly intravitreal injections of ranibizumab 0.5 mg and sham PDT; or sham intravitreal injections and active verteporfin PDT. Verteporfin (or sham) PDT was given with the initial ranibizumab (or sham) injection and every 3 months thereafter if fluorescein angiography showed persistence or recurrence of vascular leakage. A total of 423 patients were enrolled in this study (ranibizumab 0.3 mg, 140; ranibizumab 0.5 mg, 140, verteporfin PDT, 143).
** The sham ranibizumab injection control procedure involved anesthetising the eye in a manner identical to a ranibizumab intravitreal injection. The tip of a needleless syringe was then pressed against the conjunctiva and the plunger of the needleless syringe depressed.
Key outcomes are summarized in Tables 1, 2 and Figure 1. (See Table 1, Table 2 and Figure 1).


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Patients in the group treated with ranibizumab had minimal observable CNV lesion growth, on average. At Month 12, the mean change in the total area of the CNV lesion was 0.1 to 0.3 DA for ranibizumab versus 2.3 to 2.6 DA for the control arms.
Results from both trials indicated that continued ranibizumab-treatment may be of benefit also in patients who lost ≥15 letters of best-corrected visual acuity (BCVA) in the first year of treatment.
In both the MARINA and ANCHOR studies, the improvement in visual acuity seen with ranibizumab 0.5 mg at 12 months was accompanied by patient-reported benefits as measured by the National Eye Institute Visual Function Questionnaire (VFQ-25) scores. The differences between ranibizumab 0.5 mg and the two control groups were assessed with p-values ranging from 0.009 to <0.0001.
Study FVF3192g (PIER): Study FVF3192g (PIER) was a randomized, double-masked, sham-controlled, two-year study designed to assess the safety and efficacy of ranibizumab in 184 patients with neovascular AMD (with or without a classic CNV component). Patients received ranibizumab 0.3 mg or 0.5 mg intravitreal injections or sham injections once a month for 3 consecutive doses, followed by a dose administered once every 3 months. From Month 14 of the study, sham-treated patients were allowed to cross over to receive ranibizumab and from Month 19, more frequent treatments were possible. Patients treated with ranibizumab in PIER received a mean of 10 total treatments. The primary efficacy endpoint was mean change in visual acuity at 12 months compared with baseline (see Figure 2). After an initial increase in visual acuity (following monthly dosing), on average, patients dosed once every three months with ranibizumab lost visual acuity, returning to baseline at month 12. In PIER, almost all ranibizumab -treated patients (90%) maintained their visual acuity at month 12, and this effect was maintained in most ranibizumab -treated patients (82%) at Month 24. Data from a limited number of subjects that crossed over to receive ranibizumab after more than a year of sham-treatment suggested that early initiation of treatment may be associated with a better preservation of visual acuity.
Study FVF3689g (SAILOR): Study FVF3689g (SAILOR) was a Phase IIIb, single-masked, one-year multicenter study in naïve and previously treated subjects with CNV secondary to AMD. The primary study objective was to estimate the incidence of ocular and non-ocular serious adverse events in subjects treated for 12 months. Overall, 2378 patients were randomized in a 1:1 ratio to receive one intravitreal injection of 0.3 mg or 0.5 mg ranibizumab every month for three consecutive months followed by re-treatment as-needed not more often than monthly.
Overall, no imbalances between the two dose groups were observed in the frequency of ocular and non-ocular adverse events. There was a statistically non significant trend towards a higher stroke rate in the 0.5 mg group compared to the 0.3 mg group. The respective 95% CIs for the overall stroke rate were wide (0.3% to 1.3% for the 0.3 mg group vs. 0.7% to 2.0% for the 0.5 mg group). The number of strokes was small in both dose groups, and there is not sufficient evidence to conclude (or rule out) that there is a true difference in stroke rates among the treatment groups. The difference in stroke rates may be greater in patients with known risk factors for stroke, including history of prior stroke and transient ischemic attack.
Treatment of visual impairment due to DME: The efficacy and safety of ranibizumab have been assessed in two randomized, double-masked, sham- or active controlled studies of 12 months duration in patients with visual impairment due to diabetic macular edema. A total of 496 patients (336 active and 160 control) were enrolled in these studies, the majority had type II diabetes, 28 ranibizumab-treated patients had type I diabetes.
Study D2301 (RESTORE): In study D2301 (RESTORE), a total of 345 patients with visual impairment due to macular edema were randomized to receive either initial intravitreal injection of ranibizumab 0.5 mg as monotherapy and sham laser photocoagulation (n=116), combined ranibizumab 0.5 mg and laser photocoagulation (n=111), or sham injection and laser photocoagulation monotherapy. Treatment with ranibizumab was started with monthly intravitreal injections and continued until visual acuity was stable for at least three consecutive monthly assessments. The treatment was reinitiated when there was a reduction in BCVA due to DME progression. Laser photocoagulation was administered at baseline on the same day, at least 30 minutes before injection of ranibizumab, and then as needed based on Early Treatment Diabetic Retinopathy Study ETDRS criteria.
Key outcomes are summarised in Table 3 and Figure 2. (See Table 3 and Figure 2.)


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Study D2301E1 (RESTORE Extension): Study D2301E1 (RESTORE Extension) was an open-label, multi-center, 24-month extension study. 240 patients who had completed the 12-month core study entered the extension study and were treated with ranibizumab 0.5 mg pro re nata (PRN) in the same eye that was selected as the study eye in the core study. Treatment was administered monthly upon a decrease in BCVA due to DME until stable BCVA was reached. In addition, laser treatment was administered, if deemed necessary by the investigator, and based on ETDRS guidelines.
On average, 6.4 ranibizumab injections were administered per patient in the 24-month extension period in patients who were treated with ranibizumab in the core study. Of the 74 patients from the core study laser treatment arm, 59 (79%) patients received ranibizumab at some point during the extension phase. On average, these 59 patients received 8.1 ranibizumab injections per patient over the 24 months of the extension study. The proportions of patients who did not require any ranibizumab treatment during the extension phase were 19%, 25% and 20% in the prior ranibizumab, prior ranibizumab + laser, and prior laser group, respectively.
Key outcome measures are summarized in Table 4. (See Table 4.)


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VFQ-25 scores in patients who were previously treated with ranibizumab PRN in the core study stabilized during the extension phase. Those treated with laser in the core study control group, and then switched to ranibizumab PRN treatment in the extension phase, demonstrated an improvement in VFQ-25 scores.
The long-term safety profile of ranibizumab observed in this 24-month extension study is consistent with the known ranibizumab safety profile.
Study D2201 (RESOLVE): In study D2201 (RESOLVE), a total of 151 patients with macular center involvement causing visual impairment were treated with ranibizumab (6 mg/ml, n=51, 10 mg/ml, n=51) or sham (n=49) by monthly intravitreal injections until pre-defined treatment stopping criteria were met. The initial ranibizumab dose (0.3 mg or 0.5 mg) could be doubled at any time during the study after the first injection if the investigator evaluated that response to treatment was not sufficiently achieved. Laser photocoagulation rescue treatment was allowed from Month 3 in both treatment arms. The study was comprised of two parts: an exploratory part (the first 42 patients analyzed at Month 6), and a confirmatory part (the remaining 109 patients analyzed at Month 12).
Key outcomes from the confirmatory part of the study (2/3 of the patients) are summarized in Table 5 and Figure 3. (See Table 5 and Figure 3.)


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Patients treated with ranibizumab experienced a continuous reduction in central retina thickness. At month 12, the mean CRT change from baseline was -194 micrometers for ranibizumab versus -48 micrometers for sham control.
Overall, ocular and non-ocular safety findings in DME patients of both studies D2201 and D2301 were comparable with the previously known safety profile observed in wet AMD patients.
Study D2304 (RETAIN): In the phase IIIb study D2304 (RETAIN), 372 patients with visual impairment due to DME were randomized to receive either intravitreal injection of: ranibizumab 0.5 mg with concomitant laser photocoagulation on a treat-and-extend (TE) regimen (n=121), ranibizumab 0.5 mg monotherapy on a TE regimen (n=128), or ranibizumab 0.5 mg monotherapy on a pro re nata (PRN) regimen (n=123).
In all groups, treatment with ranibizumab was initiated with monthly intravitreal injections and continued until BCVA was stable for at least three consecutive monthly assessments. Laser photocoagulation was administered at baseline on the same day as the first ranibizumab injection and then as needed based on ETDRS criteria. On TE regimen, ranibizumab was then administered, at scheduled treatment at intervals of 2-3 months. On PRN regimen, BCVA was assessed monthly and ranibizumab was then administered during the same visit, if needed. In all groups, monthly treatment was re-initiated upon a decrease in BCVA due to DME progression and continued until stable BCVA was reached again. The duration of the study was 24 months.
In the RETAIN study the number of scheduled treatment visits required by the TE regimen was 40% lower than the number of monthly visits required by the PRN regimen. With both regimens, more than 70% of patients were able to maintain their BCVA with a visit frequency of ≥2 months.
Key outcome measures are summarised in Table 6. (See Table 6.)


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In DME studies, the improvement in BCVA was accompanied by a reduction over time in mean CRT in all the treatment groups.
There was no difference in the BCVA or CRT outcomes of patients in RETAIN study who received or did not receive concomitant thiazolidinediones.
Study D2303 (REVEAL): The study D2303 (REVEAL), was a 12 month, randomized, double-masked Phase IIIb trial conducted in Asian patients. Similar to the RESTORE 12 month core study in trial design and inclusion/exclusion criteria, 390 patients with visual impairment due to macular edema were randomized to receive either ranibizumab 0.5 mg injection as monotherapy and sham laser photocoagulation (n=133), ranibizumab 0.5 mg injection and laser photocoagulation (n=129), or sham injection and laser photocoagulation (n=128). Mean change in visual acuity at Month 12 compared to baseline were +6.6 letters in the ranibizumab monotherapy group, +6.4 letters in the ranibizumab plus laser group and +1.8 letters in the laser group.
Treatment of PDR: The clinical safety and efficacy of ranibizumab in patients with PDR have been assessed in Protocol S which evaluated the treatment with ranibizumab 0.5 mg intravitreal injections compared with panretinal photocoagulation (PRP). The primary endpoint was the mean visual acuity change at year 2. Additionally, change in diabetic retinopathy (DR) severity was assessed based on fundus photographs using the DR severity score (DRSS).
Protocol S was a multicentre, randomised, active-controlled, parallel-assignment, non-inferiority phase III study in which 305 patients (394 study eyes) with PDR with or without DME at baseline were enrolled. The study compared ranibizumab 0.5 mg intravitreal injections to standard treatment with PRP. A total of 191 eyes (48.5%) were randomised to ranibizumab 0.5 mg and 203 eyes (51.5%) eyes were randomised to PRP. A total of 88 eyes (22.3%) had baseline DME: 42 (22.0%) and 46 (22.7%) eyes in the ranibizumab and PRP groups, respectively.
In this study, the mean visual acuity change at year 2 was +2.7 letters in the ranibizumab group compared to -0.7 letters in the PRP group. The difference in least square means was 3.5 letters (95% CI: [0.2 to 6.7]).
At year 1, 41.8% of eyes experienced a ≥2-step improvement in the DRSS when treated with ranibizumab (n=189) compared to 14.6% of eyes treated with PRP (n=199). The estimated difference between ranibizumab and laser was 27.4% (95% CI: [18.9, 35.9]). (See Table 7.)


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At year 1 in the ranibizumab-treated group in Protocol S, ≥2-step improvement in DRSS was consistent in eyes without DME (39.9%) and with baseline DME (48.8%).
An analysis of year 2 data from Protocol S demonstrated that 42.3% (n=80) of eyes in the ranibizumab-treated group had ≥2-step improvement in DRSS from baseline compared with 23.1% (n=46) of eyes in the PRP group. In the ranibizumab-treated group, ≥2-step improvement in DRSS from baseline was observed in 58.5% (n=24) of eyes with baseline DME and 37.8% (n=56) of eyes without DME.
Treatment of visual impairment due to macular edema secondary to RVO: Study FVF4165g (BRAVO) and study FVF4166g CRUISE: The clinical safety and efficacy of ranibizumab in patients with visual impairment due to macular edema secondary to RVO have been assessed in the randomized, double-masked, controlled studies BRAVO and CRUISE that recruited subjects with BRVO (n=397) and CRVO (n=392), respectively. In both studies, subjects received either 0.3 mg or 0.5 mg intravitreal ranibizumab or sham** injections. After 6 months, patients in the sham-control arms were crossed over to 0.5 mg ranibizumab. In BRAVO, laser photocoagulation as rescue was allowed in all arms from Month 3.
Key outcomes from BRAVO and CRUISE are summarized in Tables 8 and 9, and Figures 4 and 5. (See Tables 8 and 9 and Figures 4 and 5.)


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In both studies, the improvement of vision was accompanied by a continuous decrease in the macular edema as measured by central retinal thickness.
The improvement in visual acuity seen with ranibizumab treatment at 6 and 12 months was accompanied by patient-reported benefits as measured by the National Eye Institute Visual Function Questionnaire (VFQ-25) sub-scales related to near and distance activity, a pre-specified secondary efficacy endpoint. The difference between ranibizumab 0.5 mg and the control group was assessed at Month 6 with p-values of 0.02 to 0.0002.
Study E2401 (CRYSTAL) and study E2402 (BRIGHTER): The long term (24 month) clinical safety and efficacy of ranibizumab in patients with visual impairment due to macular edema secondary to RVO were assessed in the BRIGHTER and CRYSTAL studies, which recruited subjects with BRVO (n=455) and CRVO (n=357), respectively. In both studies, subjects received a 0.5 mg ranibizumab PRN dosing regimen driven by individualized stabilization criteria. BRIGHTER was a 3-arm, randomized, active-controlled study that compared 0.5 mg ranibizumab given as monotherapy or in combination with adjunctive laser photocoagulation, to laser photocoagulation alone. After 6 months, subjects in the laser monotherapy arm could receive 0.5 mg ranibizumab. CRYSTAL was a single-arm study with 0.5 mg ranibizumab monotherapy.
Key outcome measures from BRIGHTER and CRYSTAL are shown in Table 10 and Figures 6 and 7. (See Table 10 and Figures 6 and 7.)


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In BRIGHTER, 0.5 mg ranibizumab with adjunctive laser therapy demonstrated non-inferiority to ranibizumab monotherapy from baseline to Month 24 as assessed by the mean average change in BCVA. There was no difference between the two groups in the number of ranibizumab injections administered over this period.
In both studies, a rapid and significant decrease from baseline in central retinal subfield thickness was observed at Month 1. This effect was maintained up to Month 24.
The beneficial effect of ranibizumab treatment was similar irrespective of the presence of retinal ischemia. In BRIGHTER, patients with retinal ischemia present (N=87) or absent (N=35) and treated with ranibizumab monotherapy had a mean change from baseline of +15.4 and +12.9 letters respectively, at Month 24. In CRYSTAL, patients with retinal ischemia present (N=107) or absent (N=109), treated with ranibizumab monotherapy had a mean change from baseline of +11.1 and +12.9 letters, respectively.
The beneficial effect in terms of visual improvement was observed in all patients treated with 0.5 mg ranibizumab monotherapy regardless of their disease duration in both BRIGHTER and CRYSTAL. In patients with <3 months disease duration an increase in visual acuity of 13.3 and 10.0 letters was seen at Month 1; and 17.7 and 13.2 letters at Month 24 in BRIGHTER and CRYSTAL, respectively. Treatment initiation at the time of diagnosis should be considered.
The long term safety profile of ranibizumab observed in these 24-month studies is consistent with the known ranibizumab safety profile.
Treatment of visual impairment due to CNV secondary to PM: Study F2301 (RADIANCE): The clinical safety and efficacy of ranibizumab in patients with visual impairment due to CNV in PM have been assessed based on the 12-month data of the randomized, double-masked, controlled pivotal study F2301 which was designed to evaluate two different dosing regimens of 0.5 mg ranibizumab given as intravitreal injection in comparison to verteporfin PDT (vPDT, Visudyne photodynamic therapy).
The 277 patients were randomized to one of the following arms: Group I (ranibizumab 0.5mg, dosing regimen driven by "stability" criteria defined as no change in BCVA compared to two preceding monthly evaluations);
Group II (ranibizumab 0.5mg, dosing regimen driven by "disease activity" criteria defined as vision impairment attributable to intra-or-subretinal fluid or active leakage due to the CNV lesion as assessed by OCT and/or FA);
Group III (vPDT - patients were allowed to receive ranibizumab treatment as of Month 3).
Over the 12 months of the study patients received on average 4.6 injections in Group I and 3.5 injections in Group II.
Key outcomes from F2301 are summarised in Table 11 and Figure 8. (See Table 11 and Figures 8.)


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The improvement of vision was accompanied by a reduction in central retinal thickness.
Patient-reported benefits were observed with both ranibizumab treatment arms over vPDT (p-value <0.05) in terms of improvement in the composite score and several subscales (general vision, near activities, mental health and dependency) of the VFQ-25.
Treatment of ROP in preterm infants: Study H2301 (RAINBOW): The clinical safety and efficacy of ranibizumab 0.2 mg for the treatment of ROP in preterm infants have been assessed based on the 6-month data of the randomized, open-label, 3-arm, parallel group, superiority study H2301 (RAINBOW), which was designed to evaluate ranibizumab 0.2 mg and 0.1 mg given as intravitreal injections in comparison to laser therapy. Eligible patients had to have one of the following retinal findings in each eye: Zone I, stage 1+, 2+, 3 or 3+ disease, or Zone II, stage 3+ disease, or Aggressive posterior (AP)-ROP.
In this study, 225 patients were randomized in a 1:1:1 ratio to receive intravitreal ranibizumab 0.2 mg (n=74), 0.1 mg (n=77), or laser therapy (n=74).
Treatment success, as measured by the absence of active ROP and absence of unfavorable structural outcomes in both eyes 24 weeks after the first study treatment, was highest with ranibizumab 0.2 mg (80.0%) compared to laser therapy (66.2%). The majority of patients treated with ranibizumab 0.2 mg (78.1%) did not require re-treatment with ranibizumab. The difference between ranibizumab 0.2 mg and laser was clinically relevant with an odds ratio (OR) of 2.19 (95% confidence interval (CI) [0.9932, 4.8235]). The primary endpoint did not reach statistical significance (see Table 12).


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Fewer patients in the ranibizumab 0.2 mg group switched to another treatment modality due to lack of response compared with the laser group (14.9% vs. 24.3%). Unfavorable structural outcomes were less frequently reported for ranibizumab 0.2 mg (1 patient, 1.4%) compared with laser therapy (7 patients, 10.1%). In addition, 75% of patients achieved resolution of plus disease within 8 days with ranibizumab 0.2 mg compared to 22.5 days in patients treated with laser.
Toxicology: Non-clinical safety data: Bilateral intravitreal administration of ranibizumab to cynomolgus monkeys at doses between 0.25 mg/eye and 2.0 mg/eye once every 2 weeks for up to 26 weeks resulted in dose-dependent ocular effects.
Intraocularly, there were dose-dependent increases in anterior chamber flare and cells with a peak 2 days after injection. The severity of the inflammatory response generally diminished with subsequent injections or during recovery. In the posterior segment, there were vitreal cell infiltration and floaters, which also tended to be dose-dependent and generally persisted to the end of the treatment period. In the 26-week study, the severity of the vitreous inflammation increased with the number of injections. However, evidence of reversibility was observed after recovery. The nature and timing of the posterior segment inflammation is suggestive of an immune-mediated antibody response, which may be clinically irrelevant. Cataract formation was observed in some animals after a relatively long period of intense inflammation, suggesting that the lens changes were secondary to severe inflammation. A transient increase in post-dose intraocular pressure was observed following intravitreal injections, irrespective of dose.
Microscopic ocular changes were related to inflammation and did not indicate degenerative processes. Granulomatous inflammatory changes were noted in the optic disc of some eyes. These posterior segment changes diminished, and in some instances resolved, during the recovery period. Following intravitreal administration, no signs of systemic toxicity were detected. Serum and vitreous antibodies to ranibizumab were found in a subset of treated animals.
No carcinogenicity and mutagenicity data are available.

Patizra is indicated in adults for: the treatment of neovascular (wet) age-related macular degeneration (AMD) (see Pharmacology: Pharmacodynamics under Actions).
The treatment of visual impairment due to diabetic macular edema (DME).
The treatment of proliferative diabetic retinopathy (PDR).
The treatment of visual impairment due to macular edema secondary to retinal vein occlusion (RVO).
The treatment of visual impairment due to choroidal neovascularisation (CNV) secondary to pathologic myopia (PM).
Patizra is indicated in preterm infants for: the treatment of retinopathy of prematurity (ROP) (see Pharmacology: Clinical studies under Actions).

Dosage regimen: Single-use vial (adults and preterm infants) for intravitreal use only. Use of more than one injection from a vial can lead to contamination and subsequent infection.
Patizra must be administered by a qualified ophthalmologist experienced in intravitreal injections.
The recommended dose for Patizra in adults is 0.5 mg given as a single intravitreal injection. This corresponds to an injection volume of 0.05 mL. The interval between two doses injected into the same eye should not be shorter than 1 month.
The recommended dose for Patizra in preterm infants is 0.2 mg given as a single intravitreal injection. This corresponds to an injection volume of 0.02 mL. Treatment of ROP is initiated with a single dose and can be given bilaterally on the same day. Further treatment may be administered if there are signs of disease activity. The interval between two doses injected into the same eye should not be shorter than one month.
Treatment of wet AMD: Patizra treatment in adults is initiated with a loading phase of one injection per month for three consecutive months, followed by a maintenance phase in which patients should be monitored for visual acuity on a monthly basis. If the patient experiences a loss of greater than 5 letters in visual acuity (ETDRS or one Snellen line equivalent), Patizra should be administered.
Although less effective, treatment may be reduced to one injection every three months after the first four injections if monthly injections are not feasible. Compared to continued monthly dosing, dosing every 3 months will lead to an approximate 5 letter (1-line) loss of visual acuity benefit, on average, over the following 9 months. Patients should be evaluated regularly.
Alternative dose: Treatment in adults is initiated with one injection per month until maximum visual acuity is achieved and/or there are no signs of disease activity.
Thereafter, monitoring and treatment intervals should be determined by the physician and should be based on disease activity as assessed by visual acuity and/or anatomic parameters.
Monitoring for disease activity may include clinical examination, functional testing or imaging techniques (e.g. optical coherence tomography or fluorescein angiography).
If patients are being treated according to a treat-and-extend regimen, for example, the treatment intervals can be extended stepwise until signs of disease activity or visual impairment recur. The treatment interval should be extended by two weeks at a time. If disease activity recurs, the treatment interval should be shortened accordingly.
Treatment of visual impairment due to DME: Treatment in adults is initiated with one injection per month until maximum visual acuity is achieved and/or there are no signs of disease activity.
Thereafter, monitoring and treatment intervals should be determined by the physician and should be based on disease activity as assessed by visual acuity and/or anatomic parameters.
Monitoring for disease activity may include clinical examination, functional testing or imaging techniques (e.g. optical coherence tomography or fluorescein angiography).
If patients are being treated according to a treat-and-extend regimen, for example, the treatment intervals can be extended stepwise until signs of disease activity or visual impairment recur. The treatment interval should be extended by two weeks at a time. If disease activity recurs, the treatment interval should be shortened accordingly.
Patizra and laser photocoagulation in DME: Patizra can be safely administered concomitantly with laser photocoagulation as well as in patients who have received previous laser photocoagulation. When given on the same day, Patizra should be administered at least 30 minutes after laser photocoagulation.
Treatment of PDR: Treatment in adults is initiated with one injection per month until maximum visual acuity is achieved and/or there are no signs of disease activity.
Thereafter, monitoring and treatment intervals should be determined by the physician and should be based on disease activity as assessed by visual acuity and/or anatomic parameters.
Monitoring for disease activity may include clinical examination, functional testing or imaging techniques (e.g. optical coherence tomography or fluorescein angiography).
If patients are being treated according to a treat-and-extend regimen, for example, the treatment intervals can be extended stepwise until signs of disease activity or visual impairment recur. If disease activity recurs, the treatment interval should be shortened accordingly.
Treatment of visual impairment due to CNV secondary to PM: Treatment in adults is initiated with a single injection.
If monitoring reveals signs of disease activity, further treatment is recommended.
Monitoring for disease activity may include clinical examination, optical coherence tomography (OCT) or fluorescein angiography (FA). The frequency of monitoring should be determined by the treating physician.
In the treatment of visual impairment due to CNV secondary to PM, many patients may only need one or two injections during the first year, while some patients may need more frequent treatment (see Pharmacology: Clinical studies under Actions).
Treatment of visual impairment due to macular edema secondary to RVO: Treatment in adults is given monthly and continued until maximum visual acuity is achieved, confirmed by stable visual acuity for three consecutive monthly assessments performed while on Patizra treatment.
Thereafter patients should be monitored monthly for visual acuity.
Treatment is resumed with monthly injections when monitoring indicates a loss of visual acuity due to macular edema secondary to RVO and continued until stable visual acuity is reached again for three consecutive monthly assessments.
Patizra and laser photocoagulation in Branch RVO (BRVO): Patizra can be safely administered concomitantly with laser photocoagulation. When given on the same day, Patizra should be administered at least 30 minutes after laser photocoagulation.
Treatment of ROP in preterm infants: Treatment in preterm infants is initiated with a single injection. Further treatment may be administered if there are signs of diseases activity.
Special populations: Renal impairment: Dose adjustment is not needed in patients with renal impairment (see Pharmacology: Pharmacokinetics under Actions).
Hepatic impairment: Patizra has not been studied in patients with hepatic impairment. However, as systemic exposure is negligible, no special measures are considered necessary in this population.
Pediatric Patients (below 18 years): Patizra is not recommended for use in children and adolescents due to a lack of data on safety and efficacy in these sub-populations.
Geriatric patients (65 years or above): No dose adjustment is required in the elderly.
Mode of administration: As with all medicinal products for parenteral use, Patizra should be inspected visually for particulate matter and discoloration prior to administration.
The injection procedure should be carried out under aseptic conditions, which includes the use of surgical hand disinfection, sterile gloves, a sterile drape and a sterile eyelid speculum (or equivalent). Sterile paracentesis equipment should be available as a precautionary measure. The patient's medical history for hypersensitivity reactions should be carefully evaluated prior to performing the intravitreal procedure (see Contraindications). Adequate anesthesia and a broad-spectrum topical microbicide to disinfect the periocular skin, eyelid and ocular surface should be administered prior to the injection.
For information on preparation of Patizra, see Instructions for use and handling under Cautions for Usage.
In adults, the injection needle should be inserted 3.5 to 4.0 mm posterior to the limbus into the vitreous cavity, avoiding the horizontal meridian and aiming towards the centre of the globe. The injection volume of 0.05 mL is then delivered; the scleral site should be rotated for subsequent injections.
The patient's intraocular pressure must be monitored after the injection. Monitoring should consist of a check for perfusion of the optic nerve head immediately after the injection, tonometry within 30 minutes and ophthalmoscopy 2-7 days later. Patients must be instructed to report any signs of endophthalmitis to their doctor immediately (See Precautions).
In preterm infants, the injection needle should be inserted 1.0 to 2.0 mm posterior to the limbus with the needle pointing towards the optic nerve. The injection volume of 0.02 mL is then delivered.

Cases of accidental overdose have been reported from the clinical studies and post-marketing data. Adverse reactions most frequently associated with these reported cases were intraocular pressure increased and eye pain. If an overdose occurs, intraocular pressure should be monitored and treated, if deemed necessary by the attending physician.
In clinical trials doses up to 2 mg of ranibizumab in an injection volume of 0.05 mL to 0.10 mL have been administered to patients with wet AMD and DME. The type and frequency of ocular and systemic adverse events were consistent with those reported for the 0.5 mg (in 0.05 mL) Patizra dose.

Hypersensitivity to the active substance or to any of the excipients.
Patients with active or suspected ocular or periocular infections.
Patients with active intraocular inflammation.

Intravitreal injection-related reactions: Intravitreal injections, including those with Patizra, have been associated with endophthalmitis, intraocular inflammation, rhegmatogenous retinal detachment, retinal tear and iatrogenic traumatic cataract (see Adverse Reactions). Proper aseptic injection techniques must always be used when administering Patizra. In addition, patients should be monitored during the week following the injection to permit early treatment if an infection occurs. Patients should be instructed to report any symptoms suggestive of endophthalmitis or any of the previously mentioned events without delay.
In adults, transient increases in intraocular pressure (IOP) have been seen within 60 minutes of injection of Patizra (see Adverse Reactions). Sustained IOP increases have also been reported. Both intraocular pressure and the perfusion of the optic nerve head must be monitored and managed appropriately.
Arterial thromboembolic events: There is a potential risk of arterial thromboembolic events following intravitreal use of VEGF (vascular endothelial growth factor) inhibitors. In the Phase III studies, the overall frequency of arterial thromboembolic events was similar between ranibizumab and control. A numerically higher stroke rate was observed in patients treated with ranibizumab 0.5 mg compared to ranibizumab 0.3 mg or control, however, the differences were not statistically significant. The difference in stroke rates may be greater in patients with known risk factors for stroke, including history of prior stroke or transient ischemic attack. Therefore, these patients should be carefully evaluated by their physicians as to whether Patizra treatment is appropriate whether the benefit outweighs the potential risk.
Immunogenicity: As with all therapeutic proteins, there is a potential for immunogenicity with Patizra.
Bilateral treatment: Available data do not suggest an increased risk of systemic adverse events with bilateral treatment.
An immune reaction to Patizra was seen in 0-3% of patients in all treatment groups prior to treatment. Following monthly administration, low antibody titres were detected in 1-6% of patients after 12-24 months. These immunogenicity data reflect the percentage of patients in whom electrochemiluminescence test results were positive. The data were highly dependent on the sensitivity and specificity of the test. The clinical significance of immune reactions to Patizra is unclear at this time. Iritis and vitritis were reported in some patients with the highest immunoreactivity titres.
Although there was a low rate (<4%) of arterial thromboembolic events observed in the Patizra clinical trials, there is a theoretical risk of arterial thromboembolic events following intravitreal use of inhibitors of VEGF (see Adverse Reactions).
Patient populations with limited data: Patizra has not been studied in patients with active systemic infections or in patients with concurrent eye conditions such as retinal detachment or macular hole.
Effects on ability to drive and use machines: The Patizra treatment procedure may induce temporary visual disturbances, which may affect the ability to drive or use machines (see Adverse Reactions). Patients who experience these signs must not drive or use machines until these temporary visual disturbances subside.

Pregnancy: Risk summary: For ranibizumab, no clinical data on exposed pregnancies are available.
A study in cynomolgus monkeys does not indicate direct or indirect harmful effects with respect to pregnancy or embryonal/fetal development (see Pharmacology: Toxicology: Non-clinical safety data under Actions). The systemic exposure to ranibizumab is low after ocular administration, but due to its mechanism of action, ranibizumab must be regarded as potentially teratogenic and embryo-fetotoxic. Therefore, ranibizumab should not be used during pregnancy unless the expected benefit outweighs the potential risk to the fetus. For women who wish to become pregnant and have been treated with ranibizumab, it is recommended to wait at least 3 months after the last dose of ranibizumab before conceiving a child.
Animal data: In pregnant monkeys, IVT administration of ranibizumab did not elicit developmental toxicity or teratogenicity, and had no effect on the weight or structure of the placenta. However due to restrictions dictated by the IVT route of administration, the doses used in the study did not reach maternal toxicity, but achieved a multiple (up to 100-fold) with respect to human systemic exposure.
The absence of ranibizumab-mediated effects on embryo-fetal development is plausibly related to the inability of the antigen-binding fragment (Fab) to cross the placenta due to the absence of an Fc region. Nevertheless, a case was described with high maternal ranibizumab serum levels and presence of ranibizumab in fetal serum, suggesting that the anti-ranibizumab antibody acted as a (Fc region containing) carrier protein for ranibizumab, thereby decreasing its maternal serum clearance and enabling its placental transfer. The embryo-fetal development investigations were performed in healthy pregnant animals and disease (such as diabetes) may modify the permeability of the placenta towards a Fab fragment.
Lactation: Based on limited data, ranibizumab is present in human milk and may suppress the VEGF levels. The effects of ranibizumab on the breastfed infant or the effects of ranibizumab on milk production/excretion are unknown. As a precautionary measure, breast-feeding is not recommended during the use of Patizra. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Patizra and any potential adverse effects on the breastfed child from ranibizumab.
Females and males of reproductive potential: Contraception: Females of reproductive potential should use effective contraception during treatment with ranibizumab.
Infertility: The effect of Patizra on male and female fertility has not been investigated.

Summary of the safety profile: Wet AMD population: A total of 1,315 patients constituted the safety population in the three controlled phase III studies for wet AMD (FVF2598g (MARINA), FVF2587g (ANCHOR) and FVF3192g (PIER)) with 24 months exposure to ranibizumab and 440 patients were treated with recommended dose of 0.5 mg.
Serious adverse events related to the injection procedure included endophthalmitis, rhegmatogenous retinal detachment, retinal tear and iatrogenic traumatic cataract (see Precautions).
Other serious ocular events observed among ranibizumab-treated patients included intraocular inflammation and increased intraocular pressure (see Precautions).
The adverse events listed as follows in Table-13 occurred at a higher rate (at least 2 percentage points) in patients receiving treatment with ranibizumab 0.5 mg than in those receiving control treatment (sham injection as defined in Pharmacology: Pharmacodynamics under Actions) or verteporfin photodynamic therapy (PDT)) in the pooled data of the three controlled wet AMD studies. These were therefore considered potential adverse drug reactions. The safety data described as follows also include all adverse events suspected to be at least potentially related to the injection procedure or medicinal product in the 440 wAMD patients treated with 0.5 mg ranibizumab.
DME population: The safety of ranibizumab was studied in a one-year-sham-controlled trial (RESOLVE) and in a one year laser-controlled trial (RESTORE) conducted respectively in 102 and 235 ranibizumab-treated patients with visual impairment due to DME (see Pharmacology: Pharmacodynamics under Actions). The event of urinary tract infection, in the common frequency category, met the adverse reaction criteria for the table above; otherwise ocular and non-ocular events in the RESOLVE and RESTORE trials were reported with a frequency and severity similar to those seen in the wet-AMD trials.
PDR population: The safety of ranibizumab was studied for up to 24 months in Protocol S including 191 ranibizumab-treated eyes with PDR (see Pharmacology: Clinical studies under Actions). Ocular and non-ocular events observed were consistent with what would be expected in a diabetic patient population with DR, or have been reported with a frequency and severity similar to those seen in previous clinical trials with ranibizumab.
RVO population: The safety of ranibizumab was studied in two 12-month trials (BRAVO and CRUISE) conducted respectively in 264 and 261 ranibizumab-treated patients with visual impairment due to macular edema secondary to Branch RVO (BRVO) and Central RVO (CRVO), respectively (see Pharmacology: Pharmacodynamics under Actions). Ocular and non-ocular events in the BRAVO and CRUISE trials were reported with a frequency and severity similar to those seen in the wet-AMD trials.
PM population: The safety of ranibizumab was studied in the 12-month clinical trial (RADIANCE), which included 224 ranibizumab-treated patients with visual impairment due to CNV secondary to PM (see Pharmacology: Clinical studies under Actions). Ocular and non-ocular events in this trial were reported with a frequency and severity similar to those seen in the wet-AMD trials.
Tabulated summary of adverse drug reactions from clinical trials: The adverse drug reactions from clinical trials (Table 13) are listed by MedDRA system organ class. Within each system organ class, the adverse drug reactions are ranked by frequency, with the most frequent reaction first. Within each frequency grouping, adverse drug reactions are presented in order of decreasing seriousness. In addition, the corresponding frequency category for each adverse drug reaction is based on the following convention: 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), very rare (<1/10,000). (See Table 13).


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A meta-analysis of pooled safety data from completed, randomized, double masked global studies showed a higher incidence rate of non-serious, non-ocular wound infection/inflammation in DME patients treated with ranibizumab 0.5 mg (1.85/100 patient years) compared to control (0.27/100 patient years). The relationship to ranibizumab remains unknown.
Retinopathy of Prematurity (ROP) population: The safety of ranibizumab 0.2 mg was studied in the 6-month clinical trial (RAINBOW), which included 73 ranibizumab-treated preterm infants with ROP (see Pharmacology: Clinical studies under Actions). Ocular events observed in the RAINBOW trial were consistent with those seen in adults treated with ranibizumab 0.5 mg. In general, the non-ocular events in this trial were consistent with what would be expected for this patient population with multiple comorbidities due to prematurity.

No formal interaction studies have been performed.
In clinical trials for treatment of visual impairment due to DME, the outcome with regards to visual acuity or central retinal thickness in patients treated with Patizra was not affected by concomitant treatment with thiazolidinediones (see Pharmacology: Clinical studies under Actions).
For the adjunctive use of laser photocoagulation and Patizra in DME and BRVO, see Pharmacology: Clinical studies under Actions and Dosage & Administration.

Instructions for use and handling: Vials (adult and preterm infants): Vials are for single use only (see Dosage & Administration). After injection any unused product must be discarded.
The vial is sterile. Do not use the vial if the packaging is damaged. The sterility of the vial cannot be guaranteed unless the packaging seal remains intact. Do not use the vial if the solution is discolored, cloudy, or contains particulates.
For preparation and intravitreal injection, the following single-use medical devices are needed: a 5 micrometer filter needle (18G); a 1 mL sterile syringe; an injection needle (30G x 1/2 inch).
The 1 mL sterile syringe and the injection needle are not supplied in the Patizra pack that contains the vial and the filter needle.
To prepare Patizra for intravitreal administration, adhere to the following instructions: Before withdrawal, remove the vial cap and clean the vial septum (e.g. with 70% alcohol swab).
Attach the 5 micrometer filter needle (18 G) to a 1 mL syringe using aseptic technique. Push the blunt filter needle into the centre of the vial stopper until the needle touches the bottom edge of the vial.
Withdraw all the liquid from the vial, keeping the vial in an upright position, slightly inclined to ease complete withdrawal.
Ensure that the plunger rod is drawn back sufficiently when emptying the vial in order to completely empty the filter needle.
Leave the blunt filter needle in the vial and disconnect the syringe from the blunt filter needle. The filter needle should be discarded after withdrawal of the vial contents and should not be used for the intravitreal injection.
Aseptically and firmly attach an injection needle (30G x 1/2 inch) to the syringe.
Carefully remove the cap from the injection needle without disconnecting the injection needle from the syringe.
Note: Grip at the yellow hub of the injection needle while removing the cap.
Carefully expel the air from the syringe and adjust the dose to the appropriate mark on the syringe. The dose for adults is 0.05 mL. The dose for preterm infants is 0.02 mL. The syringe is ready for injection.
Note: Do not wipe the injection needle. Do not pull back on the plunger.
After injection, do not recap the needle or detach it from the syringe. Dispose of the used syringe together with the needle in a sharps disposal container or in accordance with local requirements.
Any unused product or waste material should be disposed of in accordance with local requirements.
Incompatibilities: In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

Store in a refrigerator (2°C to 8°C).
Do not freeze.
Keep the vial in the outer carton in order to protect from light.
Prior to use, the unopened vial may be kept at room temperature (25°C) for up to 24 hours.

Other Eye Preparations

S01LA04 - ranibizumab ; Belongs to the class antineovasculatisation agents. Used in the management of neovascular macular degeneration.

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